Scott,
there was a most interesting article in New Scientist (sadly not accessible on their website) about a new theory concerning the causation of Alzheimer's, which seems to throw serious doubt on current therapies (eg Elan's) aimed at the disease plaques (which are suggested to be merely symptomatic rather than causal). I would be most interested in your opinion, as I completely lack the background to make any serious comment.
Ashley Bush of the Massachussets General Hospital postulates that it is triggered by cellular conditions (eg mild acidosis) which prevent zinc binding to a protein in the brain.
(As I understand it...) the AB (that should be beta, but I haven't worked out how to type Greek letters...) protein, which is normally an antioxidant when it binds copper and zinc, becomed a pro-oxidant when zinc is absent, producing hydrogen peroxide. The AB42 form, found in large quantities in the brains of Alzheimer's patients, is both a more powerful anti-oxidant than the normal AB40, and considerably more efficient at producing hydrogen peroxide in the absence of zinc. The theory suggests a snowball effect, where the more powerful antioxidant AB42 is produce in response to oxidative stress, but, given conditions where it can't readily bind zinc, creates greater oxidative stress, promoting further production.
The parallels with SOD1, implicated in ALS, are pointed out. Interestingly, similar mechanisms are also been suggested for Parkinsons and also prion diseases such as BSE and CJD.
References given were -
"Metal & neuroscience" by Ashley Bush in Current opinion in Chemical Biology, vol 4, p 184 (2000)
"Oxidative Stress & Alzheimer disease" by Yves Christen in American Journal of Clinical Nutrition, vol 71 p621S (2000)
(neither of which I have been able to access)
and the article copied below -
J Biol Chem, Vol. 274, Issue 52, 37111-37116, December 24, 1999
Cu(II) Potentiation of Alzheimer A Neurotoxicity
CORRELATION WITH CELL-FREE HYDROGEN PEROXIDE PRODUCTION AND METAL REDUCTION*
Xudong Huangab, Math P. Cuajungcoa, Craig S. Atwooda, Mariana A. Hartshorna, Joel D. A. Tyndallc, Graeme R. Hansond, Karen C. Stokese, Michael Leopolde, Gerd Multhaupf, Lee E. Goldsteina, Richard C. Scarpaa, Aleister J. Saundersa, James Lima, Robert D. Moirgh, Charles Glabei, Edmond F. Bowdene, Colin L. Mastersj, David P. Fairliec, Rudolph E. Tanzig, and Ashley I. Bushak
From the a Laboratory for Oxidation Biology, Genetics and Aging Unit, and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the g Genetics and Aging Unit and Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the f ZMBH-Center for Molecular Biology, Heidelberg, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany, the e Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, the i Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92717, the j Department of Pathology, University of Melbourne, and Neuropathology Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia, the c Centre for Drug Design and Development and the d Centre for Magnetic Resonance, University of Queensland, Brisbane, Queensland 4072, Australia
Oxidative stress markers as well as high concentrations of copper are found in the vicinity of A amyloid deposits in Alzheimer's disease. The neurotoxicity of A in cell culture has been linked to H2O2 generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity exhibited by A in cell culture. The potentiation of toxicity is greatest for A1-42 > A1-40 mouse/rat A1-40, corresponding to their relative capacities to reduce Cu(II) to Cu(I), form H2O2 in cell-free assays and to exhibit amyloid pathology. The copper complex of A1-42 has a highly positive formal reduction potential (+500-550 mV versus Ag/AgCl) characteristic of strongly reducing cuproproteins. These findings suggest that certain redox active metal ions may be important in exacerbating and perhaps facilitating A-mediated oxidative damage in Alzheimer's disease.
------------------------------------------------------------------------
* This work was supported in part by grants from Prana Corp.; NIA, National Institutes of Health; Alliance for Aging Research (Paul Beeson Physician Faculty Scholar in Aging research award to A. I. B.); International Life Sciences Institute; the National Health and Medical Research Council of Australia; the Australian Research Council; and the Commonwealth of Massachusetts Research Center
INTRODUCTION
Oxidative damage in the neocortex coincides with A accumulation both in Alzheimer's disease (AD)1 (1) and in A amyloid-bearing transgenic mice (2), but the mechanisms of oxidation are unknown. The possibility that A accumulation causes oxidation, perhaps by radical formation (3), has been explored, but the nature of the chemistry involved in generating A-associated oxidation products such as lipid peroxides (4) remains to be elaborated. In culture, A-induced neurotoxicity is characterized by elevated cellular H2O2 and is combated by antioxidants such as vitamin E and catalase (5). The origin of the toxic H2O2 is unknown.
Recently, we reported that Fe(III) interacts directly with A1-42 and A1-40 to produce H2O2 and TBARS formation in a cell-free manner in vitro, through reduction of the metal ion (6), suggesting that a source of the H2O2 that mediates toxicity in cell cultures exposed to A is extracellular. Cu(II)and Fe(III) have been found in abnormally high concentrations in amyloid plaques (0.4 and 1 mM, respectively) and AD-affected neuropil (7), and copper-selective chelators have been shown to dissolve A deposits extracted from AD post-mortem brain specimens (8). Therefore, these metal ions may be important cofactors in A-associated oxidative damage. Importantly, we have also reported that the generation of both Cu(II) and Fe(III)-mediated TBARS is greatest for A1-42 > A1-40 rat A1-40 (6). This rank order is of interest because it mirrors the relative participation of the peptides in amyloid neuropathology, and because the most active one (A1-42) is overproduced in familial AD (9). Rats and mice do not develop amyloid (10), even in mice transgenic for familial-AD linked mutant presenilin that overexpress endogenous mouse A1-42 (11), probably due to the three amino acid substitutions in their homologue of A (Arg5 Gly, Tyr10 Phe, and His13 Arg) (12).
Although Fe(III) mediates and potentiates A1-40 toxicity in cell culture (13), it is not clear whether this is due to metal interaction with the peptide or due to a nonspecific increase in reactive oxygen species (ROS) generation within the cell. Redox active metal ions, such as Cu(II) and Fe(III), play an obligatory role in generating ROS, and in mediating ROS-induced damage (e.g. the Fenton reaction) (14, 15). Similarly, the Cu(II) and Fe(III) enhancement of dichlorofluorescein (DCF)-reactive oxygen species generated by A25-35 treatment of post-mitochondrial rat cerebrocortex (16) could be due to catalytically enhanced ROS generation within the tissue, rather than due to metal interaction with the peptide.
Cu(II) causes the peptide to aggregate to a greater extent than Fe(III) (A1-42 > A1-40 > rat A1-40) (17), a property that may be related to the relative affinities of the metal ions for A. We hypothesize that if such redox active metal ions bind to A peptides with high affinity and become more oxidizing, they may potentiate A-induced cytotoxicity. Furthermore, if the redox competence of A is responsible for its neurotoxicity, then toxicity should be greatest for A1-42 > A1-40 > rat A1-40. A1-42 has been reported to be more neurotoxic than A1-40 (18), but a comparison of the neurotoxicity of these three peptides, or the effects of Cu(II) upon the potentiation of their respective toxicities in culture, has not yet been reported to our knowledge.
Here we report that, in the presence of Cu(II), A is indeed redox-competent (A1-42 > A1-40 rat A1-40), and that a series of electron transfer reactions occur when Cu(II) binds to A, including reduction to Cu(I) and consequent O2-dependent, cell-free peroxide formation. These changes correlate with a striking potentiation in the neurotoxicities of the respective A species in cell culture, supporting an extracellular origin for the H2O2 that mediates A-induced toxicity. These data suggest that formation of an A-copper complex may be a pathophysiological interaction, and a new target for therapeutic interdiction in AD. ..." |
