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Published online 6 February 2008 | Nature | doi:10.1038/news.2008.551
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Window opened on Alzheimer's conundrum
Mouse-brain study shows protein plaques to be a cause of the problem.
The brain protein plaques characteristic of Alzheimer’s disease can form extraordinarily fast, and seem to be the starting point of further degeneration in the brain — at least in mice.
The results, published today in Nature1, help to settle a long-standing debate about whether such plaques are a primary cause or a symptom of Alzheimer's, and may have implications for how the disease is treated.
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It's good that there will be prophylactic therapies for alzheimers coming out soon. However I wonder why these plaques form to begin with. Everything happens for a reason, and there must be a reason for plaque formation. The problem with modern medicine is that it spends too much time moderating symptoms rather than trying to solve problems. Amyloid plaques are a symptom of something and if we inhibit them, it is very likely that the underlying problem will manifest itself somehwere else. Playing whack-a-mole with disease is not good medicine. Ken www.kenstech.com
I am not an expert or anything by any means. But if you scan the literature, there are papers that give explanations to as why plague forms. Mutations in Presenilin, which is a subunit in Gamma secretase that cleaves amyloid, can cause amyloid to build up. And then there are also many papers on Gamma secretase inhibitors.
Since the research in mice has addressed the plaque versus dementia/pathology issue, I would want to know what role the microglia/inflammation play? Also, does the accumulation of plaque in bulk result in the destruction of neurons or do pro-inflammatory chemokines contribute to neuronal injury in Alheimers? Ijaz S. Jamall, Ph.D., DABT
The initial discovery of the fast growth of beta-Amyloid plaques in transgenic mice made by Professor Hyman's student R. H. Christie with our collaboration in optimizing their multiphoton microscopy imaging and analysis of their data, [J. Neuroscience 21 (3)858-864, 2001] was such a surprise that few have noticed it. Thus we are delighted by these new more precise results that may now focus research attention on the initial nucleating steps of Amyloid formation and their early consequences. Posted by: Watt W. Webb | 13 Feb, 2008
Amyloid beta peptides constitute an intriguing class of molecules that self-assemble into stable, ordered structures, and their formation reminiscent of the natural phenomenon of positive cooperative assembly. In general, this cooperativity is regulated by an allosteric effect that favors additional ligand participation in future binding events, so that interactive assemblies once formed support exponential rates of subsequent growth. In biology this phenomenon is widely observed all the way from the ionic to the molecular level – from the cooperative binding of calcium ions regulating the intercellular adhesive actions of transmembrane cadherins [1] to the allosteric cooperativity of protein kinase A generated by nucleotide and substrate positioning [2]. Interestingly allosteric cooperativity of ligand binding may be disrupted by single amino acid mutations, for example the (Y204A) site change in protein kinase A, suggesting that relatively subtle changes in ligand topography abruptly attenuates the cooperativity mechanism. The addition to Meyer-Luehmann et al.’s innovative study system [3] of amyloid peptides with mutations or other interruptive molecules that fail to support cooperative assembly may be an attractive pharmacological strategy to alter the kinetics of rapid plaque growth and the onset of Alzheimer neuropathology. [1] Courjean O, Chevreux G, Perret E, Morel A, Sanglier S, Potier N, Engel J, Dorsselaer AV, Feracci H. Modulation of E-Cadherin Monomer Folding by Cooperative Binding of Calcium Ions. Biochemistry Jan 31; epub (2008); [2] Masterson LR, Mascioni A, Traaseth NJ, Taylor SS, Veglia G. Allosteric cooperativity in protein kinase A. Proc Natl Acad Sci U S A 105:506-11 (2008); [3] Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451:720-4 (2008). WJ Lukiw, PhD, LSU Neuroscience Center, New Orleans LA 70112