Silicon Investor - Indications - Neurodegenerative

[nigel bates] NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropat...

nigel bates — 1/26/2020 7:30:42 AM

NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats
content.iospress.com

[nigel bates] I know - but perhaps interesting, as it seems like a concept which might be read...

nigel bates — 1/4/2019 4:53:14 AM

I know - but perhaps interesting, as it seems like a concept which might be readily tested in CJD ?

[scaram(o)uche] Interesting, thanks! Mouse AD models certainly haven't translated to human succ...

scaram(o)uche — 1/3/2019 2:26:03 PM

Interesting, thanks! Mouse AD models certainly haven't translated to human success, however.

[nigel bates] Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Pro...

nigel bates — 1/3/2019 8:05:22 AM

Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists

cell.com

Summary

Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric ß-amyloid peptide (Aßo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer’s disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with Aßo. A polymeric degradant of an antibiotic targets Aßo binding sites on PrPC with low nanomolar affinity and prevents Aßo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly [4-styrenesulfonic acid-co-maleic acid], PSCMA) origin. Association of PSCMA with PrPC prevents Aßo/PrPC-hydrogel formation, blocks Aßo binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1?E9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE....

[tuck] Possible new approach to Huntington's and others, via phosphatases(! because thi...

tuck — 8/23/2018 8:37:24 PM

Possible new approach to Huntington's and others, via phosphatases(! because this has been an undruggable target to this point). Assignee is a British institution. Wonder who will license it:

Selective inhibitor of the R15B phosphatase regulatory subunit

A brief note on the implications from Cell:

Raphin1

Cheers, Tuck

[mopgcw] Interesting progress on MS -- pnas.org

mopgcw — 2/23/2018 10:35:35 AM

[specboy2012] Anyone here follow PMN on the TSX? They are doing some great work on a cure or A...

specboy2012 — 1/20/2018 5:41:53 PM

Anyone here follow PMN on the TSX? They are doing some great work on a cure or AD....So far they are on track not setbacks. It started to move a bit Friday but passing it on.

[nigel bates] Tau burden and the functional connectome in Alzheimer’s disease and progressive ...

nigel bates — 1/5/2018 8:12:07 AM

Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

Thomas E Cope Timothy Rittman Robin J Borchert P Simon Jones Deniz Vatansever Kieren Allinson Luca Passamonti Patricia Vazquez Rodriguez W Richard Bevan-Jones John T O'Brien ...

Brain, awx347, doi.org

Published: 05 January 2018

Abstract

Alzheimer’s disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer’s disease, neuropathology and atrophy preferentially affect ‘hub’ brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer’s disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer’s disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer’s disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker ‘small-world’ properties. Conversely, in PSP, unlike in Alzheimer’s disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer’s disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

[scaram(o)uche] Brain. 2015 Jul 21. pii: awv214. [Epub ahead of print] Altered PDE10A expressio...

scaram(o)uche — 8/5/2015 5:39:24 PM

Brain. 2015 Jul 21. pii: awv214. [Epub ahead of print]

Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

Niccolini F1, Haider S2, Reis Marques T3, Muhlert N4, Tziortzi AC5, Searle GE5, Natesan S3, Piccini P6, Kapur S3, Rabiner EA7, Gunn RN8, Tabrizi SJ2, Politis M9.

11 Neurodegeneration Imaging Group, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
23 Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
34 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
45 School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, UK 6 School of Psychological Sciences, University of Manchester, Manchester, UK.
57 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
62 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
77 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK 8 Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King s College London, London, UK.
82 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK 7 Imanova Ltd., Centre for Imaging Sciences, Hammersmith Hospital, London, UK.
91 Neurodegeneration Imaging Group, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK marios.politis@kcl.ac.uk.

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

[scaram(o)uche] Antibody against early driver of neurodegeneration cis P-tau blocks brain injury...

scaram(o)uche — 7/15/2015 2:47:38 PM

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Asami Kondo, Koorosh Shahpasand, Rebekah Mannix, Jianhua Qiu, Juliet Moncaster, Chun-Hau Chen, Yandan Yao, Yu-Min Lin, Jane A. Driver, Yan Sun, Shuo Wei, Man-Li Luo, Onder Albayram, Pengyu Huang, Alexander Rotenberg, Akihide Ryo, Lee E. Goldstein, Alvaro Pascual-Leone, Ann C. McKee, William Meehan, Xiao Zhen Zhou & Kun Ping Lu

Nature (2015) doi:10.1038/nature14658
Received 17 June 2014 Accepted 11 June 2015 Published online 15 July 2015

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

[tuck] [Is gamma secretase even a good target in Alzheimer's?] >>Presenilin-1 Knockin ...

tuck — 3/9/2015 12:42:49 PM

[Is gamma secretase even a good target in Alzheimer's?]

>>Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Dan Xia
,
Hirotaka Watanabe
,
Bei Wu
,
Sang Hun Lee
,
Yan Li
,
Evgeny Tsvetkov
,
Vadim Y. Bolshakov
,
Jie Shen5
,
Raymond J. Kelleher III5

5Co-senior author

DOI: dx.doi.org

Highlights

•FAD-linked Presenilin-1 mutations cause complete loss of PS1 function in vivo•FAD-linked Presenilin-1 mutations abolish ?-secretase activity•FAD-linked Presenilin-1 mutations impair hippocampal memory and synaptic function•FAD-linked Presenilin-1 mutations cause age-dependent neurodegeneration

SummaryPresenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1-/- mice. Neither mutation altered Psen1 mRNA expression, but both abolished ?-secretase activity. Heterozygosity for the KI mutation decreased production of Aß40 and Aß42, increased the Aß42/Aß40 ratio, and exacerbated Aß deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.<<

In other words, these mutations caused the mice to develop AD in spite of having y-secretase activity abolished.

Cheers, Tuck

[tnsaf] SI's link massager has two problems that I know of: - It converts upper-case le...

tnsaf — 1/26/2015 5:38:48 PM

SI's link massager has two problems that I know of:
- It converts upper-case letters to lower-case
- Some non-alphanumeric characters, such as the apostrophe in your link, cause it to terminate prematurely

[sense] That's odd... I'd noted the link got mangled... so I re-did it with a modificati...

sense — 1/26/2015 5:28:26 PM

That's odd... I'd noted the link got mangled... so I re-did it with a modification of the original post and checked to see that it had posted it correctly... and now its mangled, again?

Anyone who wants can cut and paste the link from your restatement of it... Thanks.

[tnsaf] The SI link massager destroyed that link. Try copying and pasting this one-http:...

tnsaf — 1/26/2015 5:22:02 PM

The SI link massager destroyed that link. Try copying and pasting this one-http://www.wfs.org/futurist/2014-issues-futurist/september-october-2014-vol-48-no-5/unraveling-alzheimer%E2%80%99s-mystery

[sense] Unraveling the Alzheimer’s Mystery wfs.org’s-mystery

sense — 1/24/2015 1:52:06 AM

[tnsaf] Rescuing the Golgi put brakes on Alzheimer's progression American Society for Ce...

tnsaf — 12/23/2014 11:56:50 AM

Rescuing the Golgi put brakes on Alzheimer's progression
American Society for Cell Biology
eurekalert.org

Alzheimer's disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aß), overwhelm neurons. An apparent side effect of accumulating Aß in neurons is the fragmentation of the Golgi apparatus, the part of the cell involved in packaging and sorting protein cargo including the precursor of Aß. But is the destruction the Golgi a kind of collateral damage from the Aß storm or is the loss of Golgi function itself part of the driving force behind Alzheimer's? This was the question for Yanzhuang Wang, Gunjan Joshi, and colleagues at the University of Michigan, Ann Arbor, as they set out to uncover the mechanism damaging the Golgi, using a transgenic mouse and tissue culture models of AD to look at what was going on.

The unsurprising part of the answer was that rising levels of Aß do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part of the answer was that Golgi function can be rescued by blocking cdk5 or shielding its downstream target protein in the Golgi, GRASP65. The even more surprising answer was that rescuing the Golgi reduced Aß accumulation significantly, apparently by re-opening a normal protein degradation pathway for the amyloid precursor protein (APP). To Wang et al, this suggested an entirely new line of attack for drugs hoping to slow AD progression.

Speaking at the ASCB/IFCB Meeting in Philadelphia, the researchers now say that Golgi fragmentation is in itself a major--and until now an unrecognized--mechanism through which Aß extends its toxic effects. They believe that as Aß accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aß production. This is a classic "deleterious feedback circuit," they say. By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed. "Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment," the Michigan researchers report.

###

Golgi defects in Alzheimer's disease G. Joshi1, Y. Chi1, Z. Huang1, Y. Wang1; 1Dept. of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI

Poster 2103

Board Number: B626

Golgi defects in Alzheimer’s disease.

G. Joshi1, Y. Chi1, Z. Huang1, Y. Wang1;

1Dept. of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI

Golgi fragmentation occurs in neurons of patients with Alzheimer’s disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1?E9 transgenic mouse and tissue culture models. Our results suggest that Aß accumulation leads to Golgi fragmentation by activating cdk5, which in turn phosphorylates GRASP65 and perhaps other key proteins critical for maintaining Golgi morphology. Significantly, rescue of Golgi structural defects by inhibiting cdk5 or by expressing nonphosphorylatable mutants of GRASP65 reduces Aß secretion by elevating nonamyloidogenic APP cleavage. These results reveal Golgi fragmentation as an important mechanism through which Aß may exert its toxic effects. A major potential unrecognized source of Aß toxicity may be that it compromises Golgi integrity and perturbs the proper trafficking and processing of many proteins essential for neuronal function. We hypothesize that in AD, Aß accumulation promotes Golgi defects, which in turn accelerate APP trafficking and Aß production; this deleterious feedback circuit would impair the integrity of the secretory pathway and thereby compromise neuronal cell function. Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.

[scaram(o)uche] Neurobiol Dis. 2014 Dec 5. pii: S0969-9961(14)00370-2. doi: 10.1016/j.nbd.2014.1...

scaram(o)uche — 12/20/2014 1:27:27 PM

Neurobiol Dis. 2014 Dec 5. pii: S0969-9961(14)00370-2. doi: 10.1016/j.nbd.2014.11.024. [Epub ahead of print]

Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.

Martinez AA1, Morgese MG2, Pisanu A3, Macheda T1, Paquette MA1, Seillier A1, Cassano T4, Carta AR5, Giuffrida A6.

1Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
2Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA; Department of Biomedical Sciences, University of Foggia, Viale Luigi Pinto 1, Foggia 71100, Italy.
3Institute of Neuroscience, National Research Council of Italy (CNR), Cagliari, Italy.
4Department of Biomedical Sciences, University of Foggia, Viale Luigi Pinto 1, Foggia 71100, Italy.
5Department of Biomedical Sciences, University of Cagliari, Italy.
6Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: Giuffrida@uthscsa.edu.

Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPAR? subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPAR? may represent a new pharmacological target for the treatment of LID.

[sense] Scientists locate homing signal in brain, explaining why some people are better ...

sense — 12/19/2014 5:27:06 PM

Scientists locate homing signal in brain, explaining why some people are better navigators
medicalxpress.com

[scaram(o)uche] Proc Natl Acad Sci U S A. 2014 May 19. pii: 201400988. [Epub ahead of print] A ...

scaram(o)uche — 5/21/2014 8:47:17 AM

Proc Natl Acad Sci U S A. 2014 May 19. pii: 201400988. [Epub ahead of print]

A restricted population of CB1 cannabinoid receptors with neuroprotective activity.

Chiarlone A1, Bellocchio L1, Blázquez C1, Resel E1, Soria-Gómez E2, Cannich A2, Ferrero JJ3, Sagredo O4, Benito C5, Romero J5, Sánchez-Prieto J3, Lutz B6, Fernández-Ruiz J4, Galve-Roperh I1, Guzmán M7.

Abstract
The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.

[tuck] >>Do current therapeutic anti-Aß antibodies for Alzheimer’s disease en...

tuck — 5/9/2014 11:58:14 AM

>>Do current therapeutic anti-Aß antibodies for Alzheimer’s disease engage the target?

Acta Neuropathologica
May 2014

Andrew D. Watt, Gabriela A. N. Crespi, Russell A. Down, David B. Ascher, Adam Gunn, Keyla A. Perez, Catriona A. McLean, Victor L. Villemagne, Michael W. Parker, Kevin J. Barnham,

Abstract
Reducing amyloid-ß peptide (Aß) burden at the pre-symptomatic stages of Alzheimer’s disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aß is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aß in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aß with high affinity. All of the antibodies were able to bind Aß in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aß species, the Aß detected using solanezumab was barely above detection limits while crenezumab did not detect any Aß. None of the antibodies were able to detect any Aß species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aß related proteins. Bapineuzumab demonstrated target engagement with brain Aß, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.<<

Cheers, Tuck

[tuck] >>Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington’...

tuck — 3/28/2014 11:55:52 AM

>>Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington’s disease

Bindu D. Paul, Juan I. Sbodio, Risheng Xu, M. Scott Vandiver, Jiyoung Y. Cha, Adele M. Snowman & Solomon H. Snyder

Nature(2014)doi:10.1038/nature13136 Received 06 May 2013 Accepted 10 February 2014 Published online 26 March 2014

Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes 1. Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G?protein Rhes binding to mHtt and enhancing its neurotoxicity 2. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine gamma-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential.<<

Cheers, Tuck

[tnsaf] Scientists Slow Development of Cell-Killing Alzheimer's Plaques [ University of ...

tnsaf — 3/28/2014 11:04:51 AM

Scientists Slow Development of Cell-Killing Alzheimer's Plaques
[
University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer's patients and appears to be a major cause of the disease.

They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer's patients—plaques that kills cells and contributes to memory loss and other Alzheimer's symptoms.

The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to "rescue" the Golgi structure.

"We plan to use this as a strategy to delay the disease development," said Yanzhuang Wang, U-M associate professor of molecular, cellular and developmental biology. "We have a better understanding of why plaque forms fast in Alzheimer's and found a way to slow down plaque formation."

The paper appears in an upcoming edition of the Proceedings of the National Academy of Sciences. Gunjan Joshi, a research fellow in Wang's lab, is the lead author.

Wang said scientists have long recognized that the Golgi becomes fragmented in the neurons of Alzheimer's patients, but until now they didn't know how or why this fragmentation occurred.

The Golgi structure has the important role of sending molecules to the right places in order to make functional cells, Wang said. The Golgi is analogous to a post office of the cell, and when the Golgi becomes fragmented, it's like a post office gone haywire, sending packages to the wrong places or not sending them at all.

U-M researchers found that the accumulation of the Abeta peptide—the primary culprit in forming plaques that kill cells in Alzheimer's brains—triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65.

Wang and colleagues rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent.

The next step is to see if Golgi fragmentation can be delayed or reversed in mice, Wang said. This involves a collaboration with the Michigan Alzheimer's Disease Center at the U-M Health System, directed by Dr. Henry Paulson, professor of neurology, and Geoffrey Murphy, assistant professor of physiology and research professor at the U-M Molecular and Behavioral Neuroscience Institute.

The collaboration was made possible by MCubed, a two-year seed funding program to fuel interdisciplinary teams of U-M faculty to pursue research with major societal impact, as well as pilot funding from the Michigan Alzheimer's Disease Center.

Date: March 17, 2014

dddmag.com

Microscope images of the Golgi structure (red) when fragmented under disease conditions. (Source: University of Michigan/Yanzhuang Wang)

[tnsaf] Where Alzheimer's Starts and How It Spreads [very good article in ScienceDaily w...

tnsaf — 12/29/2013 11:18:28 PM

Where Alzheimer's Starts and How It Spreads
[very good article in ScienceDaily with a reference to the Nature Neuroscience study
http://www.sciencedaily.com/releases/2013/12/131222160018.htm]

Dec. 22, 2013 — Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journal Nature Neuroscience.

[nigel bates] BASEL, Switzerland and DUBLIN, Ireland, Dec. 11, 2013 (GLOBE NEWSWIRE) -- Roche ...

nigel bates — 12/12/2013 5:07:22 AM

BASEL, Switzerland and DUBLIN, Ireland, Dec. 11, 2013 (GLOBE NEWSWIRE) -- Roche (SIX:RO) ( ROG.VX) ( RHHBY) and Prothena Corporation plc ( PRTA), announced today that they have entered into a worldwide collaboration to develop and commercialize antibodies that target alpha-synuclein, including PRX002, Prothena`s monoclonal antibody for the treatment of Parkinson`s disease, which is currently in preclinical development and is expected to enter Phase 1 clinical trials in patients with Parkinson`s disease in 2014.

Synuclein proteins are a family of charged proteins found throughout the body. One protein from this family, alpha-synuclein, is found extensively in neurons and is a major component of pathological inclusions that characterize several neurodegenerative disorders, including Parkinson`s disease, dementia with Lewy bodies, neurodegeneration with brain iron accumulation type 1, and multiple system atrophy, which collectively are termed synucleinopathies.

"Parkinson`s is a severely debilitating and progressive neurodegenerative disease that leads to both a gradual worsening of motor function and cognitive and behavioral alterations," said Luca Santarelli, Head of Neuroscience and Small Molecules Research at Roche. "Currently, there is no treatment that modifies its course, and by targeting one of Parkinson`s key molecular determinants, PRX002 has the potential to slowdown or reduce its progression. This approach is consistent with our strategy in other neurodegenerative diseases, such as Alzheimer`s, Huntington, Multiple Sclerosis or Spinal Muscular Atrophy, where we target the molecular pathophysiology and intervene early with the objective to slowdown or halt the progression of disease."

"We are excited to be working with Roche to develop PRX002 as a disease modifying treatment for Parkinson`s disease and potentially other synucleinopathies. Roche is a global leader in drug development with significant experience in developing drugs to treat neurological diseases," said Dale Schenk, PhD, President and Chief Executive Officer of Prothena. "By combining Roche`s expertise with our own, this collaboration will greatly enhance our development efforts with PRX002 and allow us to move forward in a more comprehensive manner. This collaboration also represents an important milestone in our growth as we continue to execute on our corporate strategy to be a leading fully-integrated biotechnology company."

Roche and Prothena will collaborate on the development of PRX002 for Parkinson`s disease and potentially other synucleinopathies. Prothena also has an option to co-promote PRX002 in the U.S. In the U.S., the companies will share all development and commercialization costs, as well as profits, on a 70/30 basis (70% Roche and 30% Prothena). Outside the U.S., Roche will have sole responsibility for developing and commercializing PRX002 and will pay Prothena up to double-digit royalties on net sales.

Under the terms of the agreement, Prothena will receive an upfront payment and near-term clinical milestone totaling $45 million. Prothena is also eligible to receive additional payments of up to $380 million upon the achievement of development, regulatory and first commercial sales milestones plus up to an additional $175 million in ex-U.S. commercial milestone payments. The total worldwide upfront and milestone payments may amount up to $600 million.

Also as part of the agreement, Roche and Prothena will initiate a research collaboration focused on optimizing early stage antibodies targeting alpha-synuclein including incorporation of Roche`s proprietary Brain Shuttle(TM) technology to increase delivery of therapeutic antibodies to the brain.

[John McCarthy] Alzheimer's Gene Tied to Brain Changes at Early Age By -- Robert Preidt, HealthD...

John McCarthy — 12/7/2013 12:52:22 PM

Alzheimer's Gene Tied to Brain Changes at Early Age
By -- Robert Preidt, HealthDay
Dec. 06, 2013 12:00AM PST

FRIDAY, Dec. 6, 2013 (HealthDay News) -- People with a high-risk gene for Alzheimer's disease can begin to have brain changes as early as childhood, according to a new study.

The SORL1 gene is one of several associated with an increased risk of late-onset Alzheimer's, the most common form of the disease. SORL1 carries the code for a specific type of receptor that helps recycle certain molecules in the brain before they develop into beta-amyloid. Beta-amyloid is a protein associated with Alzheimer's.

The gene is also involved in fat metabolism, which is linked to a different "pathway" for developing Alzheimer's, the study authors noted.

For the study, the researchers conducted brain scans of healthy people aged 8 to 86. Study participants with a specific copy of SORL1 had reductions in white matter connections that are important for memory and higher thinking. This was true even in the youngest participants.

The investigators then examined brain tissue from 189 dead people who had not had Alzheimer's, who ranged in age from less than 1 year to 92 years. Those with the specific copy of the SORL1 gene showed disruption in the code "translation" process.

Finally, the team analyzed brain tissue from 710 dead people, aged 66 to 108. Most of them had mild cognitive [thinking] impairment or Alzheimer's. The results showed that the SORL1 risk gene was associated with the presence of beta-amyloid.

The study was published online recently in the journal Molecular Psychiatry.

"We need to understand where, when and how these Alzheimer's risk genes affect the brain, by studying the biological pathways through which they work. Through this knowledge, we can begin to design interventions at the right time, for the right people," study leader Dr. Aristotle Voineskos, of the Centre for Addiction and Mental Health in Toronto, said in a center news release.

He noted that a combination of risk factors -- unhealthy diet, lack of exercise, smoking and high blood pressure combined with a person's genetic profile -- all contribute to Alzheimer's risk.

"The gene has a relatively small effect, but the changes are reliable, and may represent one 'hit', among a pathway of hits required to develop Alzheimer's disease later in life," Voineskos said.

More information

The U.S. National Institute on Aging has more about Alzheimer's disease.

Copyright © 2013 HealthDay. All rights reserved.

health.yahoo.net

[nigel bates] Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Al...

nigel bates — 10/27/2013 4:02:21 PM

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
nature.com

[John McCarthy] continued ..... bbc.co.uk Alzheimer's breakthrough hailed as 'turning point' ...

John McCarthy — 10/10/2013 7:12:40 AM

continued .....

bbc.co.uk

Alzheimer's breakthrough hailed as 'turning point'

Professor Giovanna Mallucci says the hope is to arrest the process of brain cell death

The discovery of the first chemical to prevent the death of brain tissue in a neurodegenerative disease has been hailed as the "turning point" in the fight against Alzheimer's disease.

More work is needed to develop a drug that could be taken by patients.

But scientists say a resulting medicine could treat Alzheimer's, Parkinson's, Huntington's and other diseases.

In tests on mice, the Medical Research Council showed all brain cell death from prion disease could be prevented.

Prof Roger Morris, from King's College London, said: "This finding, I suspect, will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer's disease."

He told the BBC a cure for Alzheimer's was not imminent but: "I'm very excited, it's the first proof in any living animal that you can delay neurodegeneration.

"The world won't change tomorrow, but this is a landmark study."

Cells starveThe research team at the Medical Research Council Toxicology Unit, based at the University of Leicester, focused on the natural defence mechanisms built into brain cells.

NeurodegenerationA neurodegenerative disease is one in which the cells of the brain and spinal cord are lost The functions of these cells include decision making and control of movements These cells are not easily regenerated, so the effects of diseases can be devastatingNeurodegenerative diseases include Alzheimer's, Parkinson's, multiple sclerosis and Huntington's Source: London Brain Centre
When a virus hijacks a brain cell it leads to a build-up of viral proteins. Cells respond by shutting down nearly all protein production in order to halt the virus's spread.

However, many neurodegenerative diseases involve the production of faulty or "misfolded" proteins. These activate the same defences, but with more severe consequences.

The misfolded proteins linger and the brain cells shut down protein production for so long that they eventually starve themselves to death.

This process, repeated in neurons throughout the brain, can destroy movement or memory or even kill, depending on the disease.

This process is thought to take place in many forms of neurodegeneration, so safely disrupting it could treat a wide range of diseases.

The researchers used a compound which prevented those defence mechanisms kicking in and in turn halted neurodegeneration.

Continue reading the main storyAnalysis

It is rare to get cautious scientists keen to describe a study in mice as a turning point in treating Alzheimer's.

It is early science, a lot can go wrong between a drug for mice and a drug for humans and the only published data is for prion disease, not even Alzheimer's.

So why the excitement?

It is the first time that any form of neurodegeneration has been completely halted, so it is a significant landmark. It shows that the process being targeted has serious potential.

If this can be successfully developed, which is not guaranteed, the prize would be huge.

In Parkinson's the alpha-synuclein protein goes wrong, in Alzheimer's it's amyloid and tau, in Huntington's it's the Huntingtin protein.

But the errant protein is irrelevant here as the researchers are targeting the way a cell deals with any misfolded protein.

It means one drug could cure many diseases and that really would be something to get excited about.

Alzheimer's Research UK: Is it a cure?

The study, published in Science Translational Medicine, showed mice with prion disease developed severe memory and movement problems. They died within 12 weeks.

However, those given the compound showed no sign of brain tissue wasting away.

Lead researcher Prof Giovanna Mallucci told the BBC news website: "They were absolutely fine, it was extraordinary.

"What's really exciting is a compound has completely prevented neurodegeneration and that's a first.

"This isn't the compound you would use in people, but it means we can do it and it's a start."

She said the compound offered a "new pathway that may well give protective drugs" and the next step was for drug companies to develop a medicine for use in humans.

'Very dramatic'Prof Mallucci's lab is also testing the compound on other forms of neurodegeneration in mice but the results have not yet been published.

Side effects are an issue. The compound also acted on the pancreas, meaning the mice developed a mild form of diabetes and lost weight.

Any human drug would need to act only on the brain. However, this gives scientists and drug companies a starting point.

David Allsop, professor of neuroscience at Lancaster University described the results as "very dramatic and highly encouraging" but cautioned that more research was needed to see how the findings would apply to diseases such as Alzheimer's and Parkinson's.

Dr Eric Karran, the director of research at the charity Alzheimer's Research UK, said: "Targeting a mechanism relevant to a number of neurodegenerative diseases could yield a single drug with wide-reaching benefits, but this compound is still at an early stage.

"It will be important for these findings to be repeated and tested in models of other neurodegenerative diseases, including Alzheimer's disease."

bbc.co.uk

[nigel bates] Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneratio...

nigel bates — 10/10/2013 6:27:53 AM

Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice

stm.sciencemag.org

Julie A. Moreno1, Mark Halliday1, Colin Molloy1, Helois Radford1, Nicholas Verity1, Jeffrey M. Axten2, Catharine A. Ortori3, Anne E. Willis1, Peter M. Fischer4, David A. Barrett3 and Giovanna R. Mallucci1,*
+ Author Affiliations

1MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
2GSK Oncology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
3Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
4Division of Medicinal Chemistry and Structural Biology, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
?*Corresponding author. E-mail: grm7@le.ac.uk
Abstract

During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated...

[russet] Fish Oil May Protect Against Alcohol-Related DementiaDeborah Brauser Sep 18, 20...

russet — 9/19/2013 3:08:44 PM

Fish Oil May Protect Against Alcohol-Related DementiaDeborah Brauser

Sep 18, 2013Exposure to a compound found in fish oil may protect against the development of dementia in heavy drinkers, new research suggests.

A study presented at the recent Congress of the European Society for Biomedical Research on Alcohol in Warsaw, Poland, examined rat brain cells exposed to alcohol levels equivalent to 4 times the legal driving limit.

Results showed that the cell cultures that were also exposed to omega-3 docosahexanenoic acid (DHA) showed approximately 90% less neuroinflammation and 90% less neuronal brain cell death compared with the cells that were not exposed to the fish oil compound.

"We hypothesized that omega-3 fatty acids, specifically DHA (which has been shown to neuroprotect from other acquired brain insults in the laboratory and to some degree in human studies) would suppress or prevent the neuronal degeneration due to binge alcohol exposure," principal investigator Michael A. Collins, PhD, professor in the Department of Molecular Pharmacology and Therapeutics at the Stritch School of Medicine at Loyola University, Chicago, Illinois, told Medscape Medical News.

"And basically, that is what we found," he added.

Relevant to Humans

Dr. Collins noted that although this was an animal study designed to measure neurodegeneration and related phenomena, and not a study specifically of dementia, "since brain degeneration underlies persistent or permanent dementia, the results were extrapolated to what might happen in humans."

And although he noted in a release that further studies are now needed, "fish oil has the potential of helping preserve brain integrity in abusers. At the very least, it wouldn't hurt them."

In 2011, Dr. Collins and colleagues published a meta-analysis of 143 studies showing that consuming up to 2 alcoholic drinks a day for men and 1 drink a day for women appeared to reduce the risk for dementia and cognitive impairment.

However, "too much alcohol overwhelms the cells," they noted in a release.

"Our previous work and that of others had linked neurodegeneration to 'neuroinflammatory'-like mechanisms that include oxidative stress (oxygen and nitrogen free radicals). The oxidative stress, we suspected, resulted in part from alcohol-induced excessive release of unsaturated fatty acids from brain membranes," explained Dr. Collins.

In the current study, the researchers exposed brain cell cultures from adult rats to heavy amounts of alcohol and then compared half the cells, which were further exposed to omega-3 DHA, with the other nonexposed half.

"Our results indicate excessive arachidonic acid (AA) mobilization due to increased phospholipase A2 (PLA2) levels/activity, and this appears related to elevations in astroglial aquaporin-4 (AQP4) and brain edema," write the investigators.

In other words, excessive drinking can cause higher levels of PLA2 activity, leading to excessive production of AA (a polyunsaturated omega-6 fatty acid), which in turn leads to increased AQP4/neuroinflammation and swelling of the brain.

However, inhibiting AQP4 was found to be neuroprotective to the cells.

Best Protection

Adding omega-3 DHA to the cell cultures not only significantly decreased the release of AA and the elevated levels of PLA2 and AQP4 but also decreased ADP-ribose polymerase-1 (PARP1) elevations and overall neurodamage.

Dr. Collins reported that the investigators are planning now to conduct studies that replicate the findings in intact adult rats exposed to binge-drinking levels of alcohol and that elucidate how DHA exerts its protection in the brain.

However, he stressed that helping heavy drinkers to cut back the amounts they consume or to quit altogether is the best way to protect their brains.

"We don't want people to think it's okay to take a few fish oil capsules and then continue to go on abusing alcohol," he said.

The study was supported by the Loyola University Alcohol Research Program and a grant from the United States Public Health Service.

The 14th Congress of the European Society for Biomedical Research on Alcoholism. Abstract 01.2, presented September 8, 2013.

[scaram(o)uche] An explanation for "sundowning" syndrome? If so, could you tolerize with a subc...

scaram(o)uche — 8/14/2013 10:51:54 AM

An explanation for "sundowning" syndrome? If so, could you tolerize with a subclinical dose of a tlr4 agonist, as you can for Gram negative sepsis?

Alcohol Clin Exp Res. 2013 Jul 29. doi: 10.1111/acer.12189. [Epub ahead of print]

The Cytokine mRNA Increase Induced by Withdrawal from Chronic Ethanol in the Sterile Environment of Brain is Mediated by CRF and HMGB1 Release.

Whitman BA, Knapp DJ, Werner DF, Crews FT, Breese GR.

Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Curriculum in Neurobiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

BACKGROUND:

Many neurobiological factors may initiate and sustain alcoholism. Recently, dysregulation of the neuroimmune system by chronic ethanol (CE) has implicated Toll-like receptor 4 (TLR4) activation. Even though TLR4s are linked to CE initiation of brain cytokine mRNAs, the means by which CE influences neuroimmune signaling in brain in the absence of infection remains uncertain. Therefore, the hypothesis is tested that release of an endogenous TLR4 agonist, high-mobility group box 1 (HMGB1) and/or corticotropin-releasing factor (CRF) during CE withdrawal are responsible for CE protocols increasing cytokine mRNAs.

METHODS:

Acute ethanol (EtOH; 2.75 g/kg) and acute lipopolysaccharide (LPS; 250 µg/kg) dosing on cytokine mRNAs are first compared. Then, the effects of chronic LPS exposure (250 µg/kg for 10 days) on cytokine mRNAs are compared with changes induced by CE protocols (15 days of continuous 7% EtOH diet [CE protocol] or 3 intermittent 5-day cycles of 7% EtOH diet [CIE protocol]). Additionally, TLR4, HMGB1, and downstream effector mRNAs are assessed after CE, CIE, and chronic LPS. To test whether HMGB1 and/or CRF support the CE withdrawal increase in cytokine mRNAs, the HMGB1 antagonists, glycyrrhizin and ethyl pyruvate, and a CRF1 receptor antagonist (CRF1RA) are administered during 24 hours of CE withdrawal.

RESULTS:

While cytokine mRNAs were not increased following acute EtOH, acute LPS increased all cytokine mRNAs 4 hours after injection. CE produced no change in cytokine mRNAs prior to CE removal; however, the CE and CIE protocols increased cytokine mRNAs by 24 hours after withdrawal. In contrast, chronic LPS produced no cytokine mRNA changes 24 hours after LPS dosing. TLR4 mRNA was elevated 24 hours following both CE protocols and chronic LPS exposure. While chronic LPS had no effect on HMGB1 mRNA, withdrawal from CE protocols significantly elevated HMGB1 mRNA. Systemic administration of HMGB1 antagonists or a CRF1RA significantly reduced the cytokine mRNA increase following CE withdrawal. The CRF1RA and the HMGB1 antagonist, ethyl pyruvate, also reduced the HMGB1 mRNA increase that followed CE withdrawal.

CONCLUSIONS:

By blocking HMGB1 or CRF action during CE withdrawal, evidence is provided that HMGB1 and CRF release are critical for the CE withdrawal induction of selected brain cytokine mRNAs. Consequently, these results clarify a means by which withdrawal from CE exposure activates neuroimmune function in the sterile milieu of brain.

[scaram(o)uche] Thanks for finding/posting that work! Rick

scaram(o)uche — 6/16/2013 11:12:38 AM

[nigel bates] Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatmen...

nigel bates — 6/16/2013 3:52:07 AM

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

pnas.org

Gwenaëlle Douauda,b,1, Helga Refsumb,c,d, Celeste A. de Jagerc, Robin Jacobye, Thomas E. Nicholsa,f,g,Stephen M. Smitha, and A. David Smithb,c

Edited by Marcus E. Raichle, Washington University in St. Louis, St. Louis, MO, and approved March 29, 2013 (received for review January 29, 2013)

Abstract
Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjects with high homocysteine levels are warranted to see if progression to dementia can be prevented.

[scaram(o)uche] Cell Death Dis. 2013 Apr 4;4:e580. doi: 10.1038/cddis.2013.111. Phosphoinositi...

scaram(o)uche — 4/8/2013 10:40:08 AM

Cell Death Dis. 2013 Apr 4;4:e580. doi: 10.1038/cddis.2013.111.

Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.

Brennan-Minnella AM, Shen Y, Swanson RA.

Department of Neurology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.

Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKC?), which in turn phosphorylates the p47(phox) organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKC?. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor

[scaram(o)uche] Exp Gerontol. 2013 Mar 4. pii: S0531-5565(13)00065-X. doi: 10.1016/j.exger.2013....

scaram(o)uche — 3/22/2013 11:34:38 AM

Exp Gerontol. 2013 Mar 4. pii: S0531-5565(13)00065-X. doi: 10.1016/j.exger.2013.02.025. [Epub ahead of print]

PI3-kinase/Akt/mTOR signalling: Impaired on/off switches in aging, cognitive decline and Alzheimer's disease.

Neill CO.

Department of Biochemistry, BioSciences Institute, University College Cork, Ireland.

The normal on and off switching of the PI3-K (phosphoinositide 3-kinase) /Akt pathway, particularly by its major activators insulin and IGF-1 (insulin-like growth factor-1), is a powerful integrator of physiological responses rudimentary to successful aging. This is highlighted by extensive studies showing that reducing, but not obliterating, activation of the PI3-K/Akt/mTOR signal, at several levels, can extend healthy lifespan in organisms from yeast to mammals. Moreover, aberrant control of the PI3-K/Akt axis is emerging to be a primary causative node in all major diseases of aging: cancer, type 2 diabetes mellitus (T2DM), heart disease and neurodegeneration. Aging is the major risk factor for AD, the most common dementia disorder. The integrated coordination of neuronal responses through the PI3-K/Akt pathway has significant functional impact on key events that go awry in Alzheimer's disease (AD), including: synaptic plasticity, neuronal polarity, neurotransmission, proteostasis, use-dependent translation, metabolic control and stress responses including DNA repair. Investigation of the status of the PI3-K/Akt system in brains of individuals who have had AD show aberrant and sustained activation of neuronal PI3-K/Akt/mTOR signalling is an early feature of the disease. This is mechanistically linked to progressive desensitisation of normal brain insulin and IGF-1 responses, aberrant proteostasis of Aß and tau, synaptic loss and cognitive decline in the disease. Notably, concomitantly with feedback inhibition of insulin and IGF-1 responses, increased activation of the neuronal PI3K/Akt/mTOR axis is a major candidate effector system for transmission of pathophysiological signals from Aß to tau in the context of defects in synaptic transmission that lead to cognitive decline. Therapeutic approaches targeted at either normalizing signalling through the neuronal PI3-kinase/Akt/mTOR pathway and its activation by insulin and IGF-1 have been shown to be protective against the development of AD pathology and cognitive decline in animal models of AD and some of these therapies are entering clinical trials in patients with the disease.

(Tons of stuff like this out there, this seemed like a nice "summary" abstract. If anyone finds or knows of any program that is in the clinic? Please let us know. Thanks.)

[nigel bates] Doubt cast on the efficacy of targeting alpha-synuclein to treat Parkinson's: b...

nigel bates — 3/21/2013 9:40:53 AM

Doubt cast on the efficacy of targeting alpha-synuclein to treat Parkinson's:

bloomberg.com

"...The experimental technique involves reducing levels of alpha-synuclein, a protein found in clumps in the brains of people with Parkinson’s that increases the risk of the disease. Research presented at the American Academy of Neurology meeting in San Diego shows the condition progresses more rapidly in patients with naturally low levels of the protein.

Companies including Elan Corp., Alnylam Pharmaceuticals Inc. (ALNY), NeuroPhage Pharmaceuticals Inc. and Prana Biotechnology Ltd. (PBT) have early-stage efforts under way to develop drugs aimed at alpha-synuclein. The Michael J. Fox Foundation has put more than $47 million into research targeting the protein. The results suggest patients in clinical trials to lower alpha- synuclein may be at risk, said Demetrius Maraganore, a study author."

[mopgcw] Research Offers New Hope for Multiple Sclerosis Scientists have converted huma...

mopgcw — 2/8/2013 1:38:10 PM

Research Offers New Hope for Multiple Sclerosis

Scientists have converted human skin cells into brain cells and used them to treat mice with myelin disorders, a family of diseases that includes multiple sclerosis.

The research, reported Thursday, marks another promising advance for a technique known as cell reprogramming. The approach returns mature cells to an embryonic-like state, and then transforms them into various types of fresh, healthy tissue that could be used to treat diseases.

Multiple sclerosis is the most common myelin disorder. It strikes when the body's own immune system attacks myelin, the coating around nerve fibers. That disrupts communication between cells and can cause problems related to muscle movement, balance and vision.

In the latest study, the reprogramming technique "led to the re-myelination of the complete nervous system" of diseased animals, improving their symptoms and prolonging their life, said Steven Goldman, lead author of the report and a neurologist at University of Rochester Medical Center in Rochester, N.Y.

The findings appear in the journal Cell Stem Cell.

Myelin is made in cells known as oligodendrocytes. Those, in turn, are the offspring of oligodendrocyte progenitor cells, or OPCs.

One way to tackle a malady like multiple sclerosis is to transplant healthy, lab-made OPCs into the diseased brain, which could restore the lost myelin and reverse the damage from the disease.

Dr. Goldman's team first reprogrammed human skin cells into embryonic-like stem cells. Then they identified the cascade of chemical signals used by the body to turn embryonic cells into OPCs—and replicated that process in a lab dish.

It was hard to do, mainly because OPCs form very late in the body's development, via a multistage and complex process. It took the researchers six years to decipher the signals and to produce and purify enough OPCs that would yield sufficient myelin.

The OPCs were transplanted into mice with leukodystrophy, a hereditary condition that rendered them incapable of producing myelin. (Each year, thousands of children are born in the U.S. with some form of leukodystrophy.)

In the experiment, untreated mice displayed the typical symptoms of myelin-loss as they grew older: They developed tremors, lost their sense of balance and died prematurely, often from seizures.

The treated group initially also developed tremors and other symptoms. But once the transplanted cells began to produce sufficient myelin—it took four months—their symptoms improved and they no longer died of seizures.

Dr. Goldman said he hopes to start human trials using the cell-transplantation approach in 2015.

[tnsaf] Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ame...

tnsaf — 11/25/2012 11:25:32 PM

Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis

Nature Biotechnology (2012) doi:10.1038/nbt.2434
nature.com

Received 29 May 2012 Accepted 30 October 2012 Published online 18 November 2012

Abstract
Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.

[russet] New Risk Variant for Alzheimer's Disease Discovered Megan Brooks Nov 14, 2012 ...

russet — 11/15/2012 6:30:24 PM

New Risk Variant for Alzheimer's Disease Discovered Megan Brooks

Nov 14, 2012 A new study strongly implicates a variant in the gene encoding the triggering receptor expressed on myeloid cells 2 ( TREM2) in the pathogenesis of Alzheimer's disease (AD).

TREM2 has an antiinflammatory role in the brain. "Reduced TREM2 activity may lead to brain damage through increased inflammatory response," study leader Kari Stefansson, MD, PhD, chief executive officer, deCode Genetics, Reykjavik, Iceland, said in a statement.

"This is a basic science paper and the real clinical importance may not be known for a while yet," William Thies, PhD, chief medical and scientific officer, Alzheimer's Association, cautioned in an interview with Medscape Medical News.

"This paper is very interesting, it demonstrates real progress, it applies a new technology to the field and really points to the value of basic science in terms of it developing leads to potential therapies," Dr. Thies added.

The study was published online November 14 in the New England Journal of Medicine.

Few Known AD Variants

Outside of the e4 allele of apolipoprotein E, few variants affecting the risk for the common late-onset form of AD have been found, Dr. Stefansson and colleagues note.

They obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. They imputed these variants into the genomes of 3550 patients with AD and a control population of adults who had reached age 85 without a diagnosis of AD.

The researchers identified a rare missense mutation (rs75932628-T) in the gene encoding TREM2, leading to an R47H substitution, with an allelic frequency of 0.63% in Iceland, which conferred a significant risk for AD (odds ratio [OR], 2.92; 95% confidence interval [CI], 2.09 - 4.09). The mutation had a frequency of 0.46% in the control population.

The researchers observed the same association in additional case-control series from the United States, Norway, the Netherlands, and Germany (OR, 2.90; 95% CI, 2.16 - 3.91).

They also found that carriers of rs75932628-T aged 80 to 100 years without AD had poorer cognitive function than noncarriers ( P = .003).

Attractive Drug Target

"Given the involvement of TREM2 in the phagocytic role of microglia on amyloid plaques, it is possible that reduced TREM2 activity caused by the R47H substitution may lead to brain damage through the inability of the brain to clear these toxic products," the researchers say.

Dr. Stefansson thinks TREM2 is "an attractive target for drug development."

In comments to Medscape Medical News, Dr. Thies said, "We've known for some time that inflammation is associated with Alzheimer's disease but we haven't really been able to exploit that with current drugs. The nonsteroidal anti-inflammatory drugs have sort of a checkered history in being useful for Alzheimer's disease."

"This kind of genetic study with whole genome sequencing that points to a very specific gene that is attached to a metabolic pathway really opens up the possibility of finding molecules that will work to modulate that pathway to a clinical benefit," Dr. Thies said.

It's important to note, he added, this mutation is "relatively uncommon, so people shouldn't go out and get tested for it because they won't find any place that will do it and it isn't going to do them any good."

Nonetheless, "the value of basic science is clearly established here," Dr. Thies said, adding, "we have to fund this type of research through public sources, so the need for funding at the level of the National Alzheimer's plan demands seems to me very sensible."

The study was funded by the National Institute on Aging and by the Research Council of Norway and Southeastern Norway Health Authority. A complete list of author disclosures can be found at www.NEJM.org.

N Engl J Med. Published online November 14, 2012. Full text

[scaram(o)uche] J Biol Chem. 2012 Nov 5. [Epub ahead of print] Identification of Three Residue...

scaram(o)uche — 11/7/2012 10:04:53 AM

J Biol Chem. 2012 Nov 5. [Epub ahead of print]

Identification of Three Residues Essential for 5-HT2A-mGlu2 Receptor Heteromerization and its Psychoactive Behavioral Function.

Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez Maeso J.

Mount Sinai School of Medicine, United States

Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-HT2A receptor in mouse frontal cortex. Substitution of these residues (A6774.40, A6814.44 and A6854.48) leads to absence of molecular proximity between 5-HT2A and mGlu2, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT2A agonists. Further, the allosteric functional crosstalk between the components of the 5-HT2A-mGlu2 receptor heterocomplex is up-regulated in frontal cortex of schizophrenic subjects as compared to controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer.

[John McCarthy] This is off topic but maybe interesting to some ..... Denisova at high coverage...

John McCarthy — 9/18/2012 7:44:14 PM

This is off topic but maybe interesting to some .....

Denisova at high coverage

Thu, 2012-08-30 15:25 -- John Hawks

http://johnhawks.net/weblog/reviews/denisova/denisova-high-coverage-2012.html

Science today has released the new paper on the Denisova high-coverage genome by Mattias Meyer and colleagues from Svante Pääbo's group [1]. There is a lot of material in the supplements of the new paper, and it will take some time to work through implications.

The basics are quite simple: The paper confirms the initial interpretation of the genome by David Reich and colleagues [2] in most respects. The mixture with a whole-genome sample from Papua New Guinea is estimated at 6% Denisovan ancestry. Confirming the later paper by Reich and colleagues [3], the new analysis finds no significant evidence of Denisovan ancestry in a mainland south Chinese (Han Dai) individual, and can exclude it down to a very small fraction:

However, in contrast to a recent study proposing more allele sharing between Denisova and populations from southern China, such as the Dai, than with populations from northern China, such as the Han (17), we find less Denisovan allele sharing with the Dai than with the Han (although non-significantly so, Z = –0.9) (Fig. 4B) (table S25). Further analysis shows that if Denisovans contributed any DNA to the Dai, it represents less than 0.1% of their genomes today (table S26).

That is a mystery to be explained. How did Asians end up lacking any evidence of Denisovan ancestry, when the peoples of Sahul (Australia and New Guinea) have six percent? It's nutty! The early modern humans who were the ancestors of present Sahulian peoples surely came from Asia, and they surely mixed with Denisovans there somewhere, right? But today there's no sign that present Asian peoples descended from those early Asian peoples.

We must, I think, conclude that there was at least one, and possibly several episodes of massive population movement across South and Southeast Asia.

I have recently completed a review of the analogous problem for Neandertals in Europe -- late and early Neandertals themselves appear to have been a dynamic population. I'm now working on a review of the situation in Southeast Asia. We may fundamentally have to look at the archaeological record in a new, and much more dynamic, way than has been the case.

Neandertal gene flowTo me at the moment, this is the most interesting paragraph of the new paper:

Interestingly, we find that Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z = 5.3). However, this does not appear to be due to Denisovan gene flow into the ancestors of present-day Asians, since the excess archaic material is more closely related to Neandertals than to Denisovans (table S27). We estimate that the proportion of Neandertal ancestry in Europe is 24% lower than in eastern Asia and South America (95% C.I. 12–36%). One possible explanation is that there were at least two independent Neandertal gene flow events into modern humans (18). An alternative explanation is a single Neandertal gene flow event followed by dilution of the Neandertal proportion in the ancestors of Europeans due to later migration out of Africa. However, this would require about 24% of the present-day European gene pool to be derived from African migrations subsequent to the Neandertal admixture.

This is a very interesting result, partially because it is the opposite of what we are finding. As I explained earlier this year, we are finding Europeans to share more Neandertal alleles than Asians do. The difference in our results has been much smaller than 24%; really only an increase of less than 0.5% on the whole genome, or maybe 10% relative to the overall amount in Europe (which is on the order of 3%).

My initial reaction to this difference is that it reflects the sharing of Neandertal genes in Africa. Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison. But if Africans have some gene flow from Neandertals, eliminating alleles found in Africans will create a bias in the comparison. If (as we think) some African populations have Neandertal gene flow, that probably came from West Asia or southern Europe. So as long as the present European and Asian (and Native American) samples have undergone a history of genetic drift, or if (as mentioned in the quote) they mixed with slightly different Neandertal populations, this bias will tend to make Asians look more Neandertal and Europeans less so.

Anyway, this demands further investigation. The Denisova genome makes a more compelling outgroup for these kinds of comparisons, because it is much closer to us than chimpanzees are. But it isn't really an outgroup because it shares alleles by descent with Neandertals. So it takes some clever genetics to compare the distributions of derived alleles in these genomes in terms of introgression versus incomplete lineage sorting.

Denisovan demographyIt has become possible to make some good estimates of demographic history using only a single diploid genome, using a technique developed by Li and Durbin [4]. Meyer and colleagues applied this technique to the Denisova genome, finding that its genetic history contrasts with that of living human populations:

To estimate how Denisovan and modern human population sizes have changed over time we applied a Markovian coalescent model (22) to all genomes analyzed. This shows that present-day human genomes share similar population size changes, in particular a more than two-fold increase in size before 125,000–250,000 years ago (depending on the mutation rates assumed (23), Fig. 5B). Denisovans, in contrast, show a drastic decline in size at the time when the modern human population began to expand.

There is not yet enough data from Neandertal genomes to apply the same method, but to the extent that we understand their diversity, they show a similar picture. These archaic humans in Eurasia had much, much smaller effective population sizes than the ancient population of Africa. That's not surprising, given what we understand about ancient hunter-gatherer population dynamics.

What may be a bit more surprising is the geography. We know that Neandertals of Europe and Central Asia lived in an environment that was relatively marginal for their technology and subsistence pattern. The Denisovan population could well have lived in parts of South or Southeast Asia -- subtropical and tropical areas comparable to Africa in their ecological diversity and resource richness.

We might have imagined that the Denisovan population would be more diverse than Neandertals -- that it might have been comparable in diversity to part of Africa, if not the entirety of Africa. The genome is inconsistent with that picture.

How can we explain the apparent contrast?

1. Maybe Denisovans didn't live in South or Southeast Asia at all. If not, that demands that we explain how Australians got their genes.

2. Maybe the population was geographically extensive and diverse, but the genome from Denisova Cave doesn't represent it well. If so, we might discover that Sahulians actually have even more ancestry from this group. Alternatively, we might find that the early history of the population was widely shared, but the recent history diverged between Siberian and other branches of the Denisovan-inhabited region.

3. Maybe African diversity emerged from a much more complex series of interactions than we now appreciate. The demographic model of Li and Durban doesn't encompass admixture, just the probability of gene coalescence across time. We have recently begun to appreciate the reality of ancient African population structure. If those initial African populations were more divergent from each other than Neandertals and Denisovans, their later mixture would give rise to a picture of early population expansion, even if each of them had relatively low (Denisovan-like) diversity.

This picture is already complicated. It will get more so. We have a long way to go before the archaeology of MSA and Middle Paleolithic peoples will be reconciled with these genetic models.

The "modern human" catalogI think it's tremendously interesting that the authors have compiled a list of gene variants shared by living humans that are absent from this high-coverage archaic human genome. It's a first step to identifying networks of genes that have been subject to recent evolutionary change in human ancestors.

That being said, the list of genes itself doesn't lend itself to concrete conclusions:

One way to identify changes that may have functional consequences is to focus on sites that are highly conserved among primates and that have changed on the modern human lineage after separation from Denisovan ancestors. We note that among the 23 most conserved positions affected by amino acid changes (primate conservation score = 0.95), eight affect genes that are associated with brain function or nervous system development (NOVA1, SLITRK1, KATNA1, LUZP1, ARHGAP32, ADSL, HTR2B, CBTNAP2). Four of these are involved in axonal and dendritic growth (SLITRK1, KATNA1) and synaptic transmission (ARHGAP32, HTR2B) and two have been implicated in autism (ADSL, CNTNAP2). CNTNAP2 is also associated with susceptibility to language disorders (27) and is particularly noteworthy as it is one of the few genes known to be regulated by FOXP2, a transcription factor involved in language and speech development as well as synaptic plasticity (28). It is thus tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans.

Interesting. I can imagine a Ph.D. dissertation looking into the function of each of those genes. It is surely true that in the last 300,000 years, human brains have been evolving. But why these genes as opposed to others? And how many regulatory changes (as opposed to amino acid changes) may have been further involved?

Maybe even more interesting: How many times will the human alleles be found in some other Denisovan (or Neandertal) genomes, and how often will the "archaic" allele be found in anyone living now?

A limited series of comparisons is too small to exclude that the range of variation will overlap, as fossil analysts have known for a long time. So we will need to work on extending our knowledge of the range of variation within living people, by increasing the sample of genomes representing populations around the world, particularly in Africa.

The technologyOf course, the most exciting thing about the new paper is the proof of concept for future high-coverage archaic genomes. The lab was able to generate the high-coverage sequence using its existing samples, by sequencing single-strand DNA instead of requiring double-strand DNA. This is a massive advantage when working with ancient DNA, because damage to the sequence often prevents double-stranded DNA from being amplified.

The paper makes explicit that the Denisova phalanx simply has better endogenous DNA preservation than any other specimen known. That being said, the new sequencing method has greatly increased the sequence yield from the sample:

We applied this method to aliquots of the two DNA extracts (as well as side fractions) that were previously generated from the 40 mg of bone that comprised the entire inner part of the phalanx (2, 8). Comparisons of these newly generated libraries to the two libraries generated in the previous study (2) show at least a 6-fold and 22-fold increase in the recovery of library molecules (8), which is particularly pronounced for longer molecules (fig. S4).

It would be too soon to say that a similar increase in yield will happen for other specimens, but obviously, this may bring higher coverage into reach for several specimens that are currently only sequenced at very low coverage, including the Vindija, Mezmaiskaya, and El Sidron Neandertals. We will have to wait and see how the new technique affects ancient DNA recovery going forward.

I keep telling people that I think it's exciting that research into human evolution is now pushing technology forward. It has often been that paleoanthropology uses technological advances in other fields. But with ancient DNA, we really see an organic growth of technology along with research questions about our evolution. In our work on the ancient genomes, we're making some progress pushing forward knowledge about human biology by understanding human evolution. Evolution really is the fundamental principle of biology, but using evolution to learn about biology sometimes requires traveling through time. Ancient DNA gives us a time machine bringing new insights into reach.

References
=1482]Meyer M, =1485]Kircher M, =17335]Gansauge M-T, =23]Li H, =17336]Racimo F, =1481]Mallick S, =17337]Schraiber JG, =17338]Jay F, =30]Prüfer K, =17339]de Filippo C. A High-Coverage Genome Sequence from an Archaic Denisovan Individual. Science. 2012. =1152]Reich D, =1483]Green RE, =1485]Kircher M, =1389]Krause J, =1151]Patterson N, =1150]Durand EY, =1486]Viola B, =1487]Briggs AW, =1488]Stenzel U, =1489]Johnson PLF. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature [Internet]. 2010;468:1053–1060. Available from: dx.doi.org =1152]Reich D, =1151]Patterson N, =1485]Kircher M, =3297]Delfin F, =15593]Nandineni MR, =15594]Pugach I, =15595]Ko AM-S, =15596]Ko Y-C, =15597]Jinam TA, =15598]Phipps ME. Denisova admixture and the first modern human dispersals into southeast Asia and oceania. American journal of human genetics. 2011;89(4):516-28. =23]Li H, =24]Durbin R. Inference of human population history from individual whole-genome sequences. Nature [Internet]. 2011;475:493–496. Available from: dx.doi.org

Tags:

Denisova
Neandertal DNA
ancient DNA
population structure
effective population size
Asia
Australia
New Guinea
admixture

[mopgcw] Biotechnology R. Mehrotra Multiple Sclerosis - Some thoughts on 3rd Laquinimod ...

mopgcw — 8/9/2012 2:20:59 PM

Biotechnology R. Mehrotra
Multiple Sclerosis - Some thoughts on 3rd Laquinimod PIII, More of a FINALE than a CONCERTO

Yesterday Teva and Active Biotech announced the initiation of a 3rd oral laquinimod PIII study under a SPA. The new
disability focused trial is aptly named CONCERTO, following on from the completed ALLEGRO and BRAVO PIII studies. In
the unlikely event that a fourth trial is started, we suggest it gets called FINALE. Our initial thoughts are that this study is
actually a subtly important and interesting development for the MS space:

Relapse vs. Disability-unearthing an age-old debate. Steeping back from the minutia of the trial for one moment, we remind
ourselves that the ultimate goal of physicians and patients in treating MS is the prevention of long-term disability. The
evolution of relapse rates/counts as the principal primary endpoint in the majority of clinical studies conducted over the last
two decades is a reflection of a focus on relapsing/remitting MS development for the ABCRs in the early 90s. Statistically
significant disability endpoints in these first pivotal MS studies (typically 250-400 patients) were harder to achieve in 2-year
time frames. Indeed, to this day, only Rebif and Avonex from the 1st-gen ABCR class have delayed progression claims on
their labels. Using an EDSS primary endpoint in PIII is NOT that unusual. Avonex's MS1 pivotal trial and two of three
Betaseron pivotal trials used a dual EDSS primary (time-to-progression & percentage progressed) while Tysabri's AFFIRM
trial used time-to-progression. More recently Lemtrada's CARE-MS1 and -MS2 studies used a reduction in EDSS
progression & annualized relapse rate reduction as co-primary endpoints. Enough of the author's gray-haired stories...

The CONCERTO trial has some important subtleties. Recall, the results of the previous PIII ALLEGRO and BRAVO trials
showed good EDSS but poor RR reduction. Hence, it is understandable why laquinimod's development is now focused on
disability endpoints (let's leave the debate of a putative Copaxone combination trial for another time). We note some
interesting points within the relatively short press release: 1) two doses in CONCERTO, 0.6mg and 1.2mg;

ALLEGRO/BRAVO used 0.6mg and PII studies used 0.1 to 0.6mg , 2) 1,800 patients vs. 1,000/1,200 in
ALLEGRO/BRAVO-understandable reflecting multiple doses and EDSS endpoint, 3) "For up to 24
months"...hmmm...probably reflecting a time to EDSS progression endpoint, 4) the (not-so) specific primary endpoint is
described as "disability progression as measured by EDSS"; we assume CONCERTO will use time-to-progression on
EDSS (secondary endpoint in ALLEGRO/BRAVO), and 5) no mention of secondary endpoints were given; we assume they
will include ARR (another bite at the cherry!) and MRI data. So as a final(e) comment...look a whole note on MS without the
word NIMO or a 3 buckets comment!

[John McCarthy] Chronic 'Butter Flavoring' Exposure Linked to Harmful Brain Process [graphic]Hea...

John McCarthy — 8/6/2012 3:13:42 PM

Chronic 'Butter Flavoring' Exposure Linked to Harmful Brain Process HealthDay – 57 mins ago

MONDAY, Aug. 6 (HealthDay News) -- Chronic exposure to an artificial butter flavoring ingredient, known as diacetyl, may worsen the harmful effects of a protein in the brain linked to Alzheimer's disease, according to a new study.

The findings should serve as a red flag for factory workers with significant exposure to the food-flavoring ingredient, researchers from the University of Minnesota said in the report published in a recent issue of the journal Chemical Research in Toxicology.

Diacetyl is used to give a buttery taste and aroma to common food items such as margarines, snack foods, candy, baked goods, pet foods and other products.

The investigators pointed out that previous studies have already linked diacetyl to respiratory and other health problems among workers at microwave popcorn and food-flavoring plants.

Although diacetyl forms naturally in fermented beverages, such as beer and wine, its chemical structure is similar to a substance that makes beta-amyloid proteins clump together in the brain. This clumping, the study authors noted, is a hallmark of Alzheimer's disease.

In their study, the researchers found that diacetyl also increases the amount of beta-amyloid clumping in the brain. And it worsened the beta-amyloid protein's harmful effects on nerve cells grown in a lab when the cells were exposed to the same levels of diacetyl that factory workers might be exposed to in their jobs.

The study authors pointed out that other experiments revealed that diacetyl also crosses the "blood-brain barrier," which helps protect the brain from dangerous substances. Diacetyl also prevented a beneficial protein from protecting nerve cells.

"In light of the chronic exposure of industry workers to diacetyl, this study raises the troubling possibility of long-term neurological toxicity mediated by diacetyl," Robert Vince and colleagues concluded in a news release from the American Chemical Society.

The study was funded by the Center for Drug Design research endowment funds at the University of Minnesota.

While the study found an association between chronic diacetyl exposure and certain brain protein processes, it did not prove a cause-and-effect relationship.

More information

The U.S. National Library of Medicine has more about Alzheimer's disease.

news.yahoo.com

[DewDiligence_on_SI] Gammagard shows promising results in small phase-2 extension study: siliconinve...

DewDiligence_on_SI — 7/17/2012 6:26:47 PM

Gammagard shows promising results in small phase-2 extension study:

siliconinvestor.com

[russet] Scientists Identify Protein Required to Regrow Injured Nerves in Limbs silicon...

russet — 6/21/2012 10:14:16 PM

Scientists Identify Protein Required to Regrow Injured Nerves in Limbs

siliconinvestor.com

enlarge

These are images of axon regeneration in mice two weeks after injury to the hind leg’s sciatic nerve. On the left, axons (green) of a normal mouse have regrown to their targets (red) in the muscle. On the right, a mouse lacking DLK shows no axons have regenerated, even after two weeks. (Credit: Jung Eun Shin)

ScienceDaily (June 20, 2012) — A protein required to regrow injured peripheral nerves has been identified by researchers at Washington University School of Medicine in St. Louis.

The finding, in mice, has implications for improving recovery after nerve injury in the extremities. It also opens new avenues of investigation toward triggering nerve regeneration in the central nervous system, notorious for its inability to heal.

Peripheral nerves provide the sense of touch and drive the muscles that move arms and legs, hands and feet. Unlike nerves of the central nervous system, peripheral nerves can regenerate after they are cut or crushed. But the mechanisms behind the regeneration are not well understood.

In the new study, published online June 20 in Neuron, the scientists show that a protein called dual leucine zipper kinase (DLK) regulates signals that tell the nerve cell it has been injured -- often communicating over distances of several feet. The protein governs whether the neuron turns on its regeneration program.

"DLK is a key molecule linking an injury to the nerve's response to that injury, allowing the nerve to regenerate," says Aaron DiAntonio, MD, PhD, professor of developmental biology. "How does an injured nerve know that it is injured? How does it take that information and turn on a regenerative program and regrow connections? And why does only the peripheral nervous system respond this way, while the central nervous system does not? We think DLK is part of the answer."

The nerve cell body containing the nucleus or "brain" of a peripheral nerve resides in the spinal cord. During early development, these nerves send long, thin, branching wires, called axons, out to the tips of the fingers and toes. Once the axons reach their targets (a muscle, for example), they stop extending and remain mostly unchanged for the life of the organism. Unless they're damaged.

If an axon is severed somewhere between the cell body in the spinal cord and the muscle, the piece of axon that is no longer connected to the cell body begins to disintegrate. Earlier work showed that DLK helps regulate this axonal degeneration. And in worms and flies, DLK also is known to govern the formation of an axon's growth cone, the structure responsible for extending the tip of a growing axon whether after injury or during development.

The formation of the growth cone is an important part of the early, local response of a nerve to injury. But a later response, traveling over greater distances, proves vital for relaying the signals that activate genes promoting regeneration. This late response can happen hours or even days after injury.

But in mice, unlike worms and flies, DiAntonio and his colleagues found that DLK is not involved in an axon's early response to injury. Even without DLK, the growth cone forms. But a lack of DLK means the nerve cell body, nestled in the spinal cord far from the injury, doesn't get the message that it's injured. Without the signals relaying the injury message, the cell body doesn't turn on its regeneration program and the growth cone's progress in extending the axon stalls.

In addition, it was shown many years ago that axons regrow faster after a second injury than axons injured only once. In other words, injury itself increases an axon's ability to regenerate. Furthering this work, first author Jung Eun Shin, graduate research assistant, and her colleagues found that DLK is required to promote this accelerated growth.

"A neuron that has seen a previous injury now has a different regenerative program than one that has never been damaged," Shin says. "We hope to be able to identify what is different between these two neurons -- specifically what factors lead to the improved regeneration after a second injury. We have found that activated DLK is one such factor. We would like to activate DLK in a newly injured neuron to see if it has improved regeneration."

In addition to speeding peripheral nerve recovery, DiAntonio and Shin see possible implications in the central nervous system. It is known for example, that some of the important factors regulated and ramped up by DLK are not activated in the central nervous system.

"Since this sort of signaling doesn't appear to happen in the central nervous system, it's possible these nerves don't 'know' when they are injured," DiAntonio says. "It's an exciting idea -- but not at all proven -- that activating DLK in the central nervous system could promote its regeneration."

[DewDiligence_on_SI] I would suggest that you check out other resurfacing options; some of them may e...

DewDiligence_on_SI — 5/25/2012 11:13:57 AM

I would suggest that you check out other resurfacing options; some of them may employ ceramic materials rather than all metal. There are several manufacturers of these kits; however, many orthopedic surgeons work with only one company so they may not be the best source of information about the choices available.

As you noted, the stray ions from metal-on-metal may be much ado about nothing; however, if you can eliminate a potential risk without a corresponding downside, it would seem to be prudent to investigate it. I’ll be interested to know what you find out. Good luck.

[bmaz001] Thanks, Dew. Unfortunately, the non metal-on-metal options (that I'm aware of) ...

bmaz001 — 5/25/2012 10:27:14 AM

Thanks, Dew. Unfortunately, the non metal-on-metal options (that I'm aware of) are in the 'total hip replacement' category. That approach involves lopping off a large section of the upper femur. Hip resurfacing is very different in that the 'ball' of the femur is slightly ground down and then 'capped'. The 'kit' that my surgeon uses is the Birmingham Hip Resurfacing system (BHR). If I knew that the ions resulting from the metal-on-metal contact were too minimal to affect neurodegenerative diseases, I'd go with the BHR approach. Unfortunately, I doubt that anyone really knows for sure at this point.

[DewDiligence_on_SI] There are product options for hips that do not involve metal-on-metal technology...

DewDiligence_on_SI — 5/24/2012 4:01:36 PM

There are product options for hips that do not involve metal-on-metal technology, so you should be able to avoid whatever incremental risk the stray metal ions might induce. Regards, Dew

[bmaz001] Alzheimer's, metal ions and hip resurfacing- Alzheimer's has been in my mother's...

bmaz001 — 5/23/2012 2:53:12 PM

Alzheimer's, metal ions and hip resurfacing-
Alzheimer's has been in my mother's family for at least a few generations, so I'm assuming that I may be genetically predisposed to contracting this terrible disease someday. As I've aged, I've become more curious about AD and I've read that there may be an association between AD and metal ions that have accumulated in the brain. Also, several years ago I remember stories about people throwing away their aluminum cookware because they believed that Aluminum in the blood stream might play a part in developing AD. I don't have the educational background to explore and understand the role of metal ions in the development of AD and, even if I did, I'm not certain that enough research on the matter has been published to draw any conclusions. But here's my dilemma... My left hip is arthritic to the point that I need to do something about it. Pain meds no longer help. Structurally, my preference is to have my hip 'resurfaced'. However, because current resurfacing 'kits' involve metal-on-metal interfaces (Cobalt & Chromium), I'm concerned about how the metal ions might impact the progression of AD. I'd be grateful if anyone familiar with this topic is willing to offer feedback/advice. Of course, I can always have a full hip replacement done, instead of resurfacing. Metal-on-metal interfaces aren't an issue with full hip replacements. However, I lead a very active lifestyle (biking, swimming, hiking, etc.) and my understanding is that, at 55 years of age, the resurfacing approach is the better option for me (if metal ions and AD weren't a concern). Thoughts?

[mopgcw] corrected link[url=http://the-scientist.com/2012/05/23/could-stem-cells-cure-ms/...

mopgcw — 5/23/2012 12:55:55 PM

corrected link[url=http://the-scientist.com/2012/05/23/could-stem-cells-cure-ms/]

the-scientist.com

[mopgcw] after the FDA warning on Zamboni, this is some good news: the-scientist.com

mopgcw — 5/23/2012 12:03:48 PM