Inhibiting brain protein might reverse Alzheimer’s
OFF TOPIC - and really good news ....
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to high levels of a protein known as Striatal-Enriched tyrosine Phosphatase, or STEP, as a major factor in Alzheimer’s.
Striatal-Enriched tyrosine Phosphatase, or STEP
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HARTFORD, Conn. — Yale researchers say inhibiting a protein in the brain may be key to reversing the effects of Alzheimer’s disease.
In a study published Monday in Proceedings of the National Academy of Sciences, the team of researchers points to high levels of a protein known as Striatal-Enriched tyrosine Phosphatase, or STEP, as a major factor in Alzheimer’s.
Based on previous studies that have shown an elevated activity of STEP in humans with Alzheimer’s, the Yale researchers conducted tests on two sets of mice. Both were genetically engineered to have Alzheimers, but one set was also engineered to have its STEP protein levels reduced. They found that the mice with reduced STEP were eventually able to complete mazes in the same time as mice without Alzheimer’s.
“The importance of that study is that it suggested that reducing STEP levels genetically reduces” the effects of Alzheimer’s, said Paul Lombroso, senior author of the study.
What the excess of STEP does, he said, is damage certain neurons. Specifically, the protein removes glutamate receptors on the neurons’ surface, which are crucial to forming long-term memories.
“This suggests that a too-high level of STEP, by removing glutamate receptors, is stripping away the ability to memorize and learn,” said Lombroso, professor in the Yale Child Study Center and in the Departments of Neurobiology and Psychiatry at Yale School of Medicine.
Other studies have indicated the STEP plays a similar role in schizophrenia and fragile x, a form of mental retardation.
Lombroso said the mice with reduced levels of STEP showed a complete reversal of the effects of Alzheimer’s by six months. More research, he said, is required to see if any of the symptoms of Alzheimer’s would return with more time.
Lombroso said he hopes additional research will lead to the development of a drug that could inhibit the STEP protein and treat Alzheimer’s in humans.
Asked whether excessive STEP levels play a factor in the routine dulling of the mind that often comes with aging, Lombroso said that had not been ruled out, but that no research had been conducted.
“We’re looking at whether or not there’s a disruption in STEP function in these older mice and rats, but there’s no data,” he said.
Chris Van Dyck, director of Yale’s Alzheimer’s Disease Research Unit, called the paper “exciting research.”
“We know that with Alzheimer’s disease, synaptic function is key to cognitive deficit,” said Van Dyck, who was not a part of the study. “This is an important paper that attempts to explain that.” In the process, he added, a possible treatment could realistically arise from it.
He said, though, that a good deal more research is needed to know what these results mean “because mice are not people and these Alzheimer’s mouse models are limited.”
heraldnet.com
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PubMed
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role of STEP in Alzheimer disease.
Kurup P, Zhang Y, Venkitaramani DV, Xu J, Lombroso PJ.
Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract
Amyloid beta (Abeta), the putative causative agent in Alzheimer disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Abeta downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP(61)). More recent findings confirm that STEP(61) plays an important role in Abeta-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP(61) levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP(61) is due to disruption in the normal degradation of STEP(61) by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP(61) contributes to aspects of the pathophysiology in Alzheimer disease. Exogenous application of Abeta-enriched conditioned medium (7PA2-CM) to wild-type cortical cultures results in a loss of GluN1/GluN2B subunits from neuronal membranes. Abeta-mediated NMDAR internalization does not occur in STEP knock-out cultures, but is rescued by the addition of active TAT-STEP to the cultures prior to Abeta treatment.
PMID: 20699650 [PubMed - as supplied by publisher]
ncbi.nlm.nih.gov
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NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling.
Paul S, Connor JA.
Department of Neurology, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131, USA. spaul@salud.unm.edu
Abstract
NMDA receptors regulate both the activation and inactivation of the extracellular signal-regulated kinase (ERK) signaling cascade, a key pathway involved in neuronal plasticity and survival. This bi-directional regulation of ERK activity by NMDA receptors has been attributed to opposing actions of NR2A- versus NR2B-containing NMDA receptors, but how this is implemented is not understood. Here, we show that glutamate-mediated intracellular Ca(2+) increases occur in two phases, a rapid initial increase followed by a delayed larger increase. Both phases of the Ca(2+) increase were blocked by MK-801, a non-selective NMDA receptor inhibitor. On the other hand, selective inhibition of NR2B-NMDA receptors by Ifenprodil or Ro 25-6981 blocked the delayed larger phase but had only a small effect on the rapid initial increase. The rapid initial increase in Ca(2+), presumably because of NR2A-NMDAR activation, was sufficient to activate ERK, whereas the large delayed increases in Ca(2+) mediated by NR2B-NMDARs were necessary for dephosphorylation and subsequent activation of striatal-enriched phosphatase, a neuron-specific tyrosine phosphatase that in turn mediates the dephosphorylation and inactivation of ERK. We conclude that the magnitude of Ca(2+) increases mediated through NR2B-NMDA receptors plays a critical role in the regulation of the serine/threonine and tyrosine kinases and phosphatases that are involved in the regulation of ERK activity.
PMID: 20524968 [PubMed - indexed for MEDLINE]
ncbi.nlm.nih.gov
An odd thought - don't understand all of the above
but MEMANTINE definitely has an effect on NR2B-NMDA receptor
specifically with respect to how much CALCIUM they HUMP. |
