Amyloid hypothesis

According to the amyloid hypothesis, the A 3 peptide plays a critical role in the pathogenesis of Alzheimer s disease [1]. Major forms of A 3 produced encompass 38, 40 or 42 residues. A 342 is more prone to aggregation than A 340 and in animal models an increased A[342/ A (340 ratio results in amyloid plaque pathology even when total A 3 levels are reduced [4]. The generation of A 3 is a normal process and A 3 is present in the brains and body fluids of humans throughout life. Neuronal... 

Neve, RL and Robakis, NK (1998) Amyloid disease a re-examination of the amyloid hypothesis. Trends Neurosci. 21 15-19. 

Hardy, J., and Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer s disease Progress and problems on the road to therapeutics. Science 297, 353-356. 

Figure 11.1 The amyloid hypothesis in Alzheimer s disease. The transmembrane protein amyloid precursor protein (APP) is cleaved first by f> -secretase (BACE), then by y -secretase. The resulting peptidic fragment, AfSAO/42, is liberated, leading to plaque accumulation. These plaques are associated with neuronal degeneration.

Dominguez, D. I., De Strooper, B. Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer s disease. Trends Pharmacol. Sci. 2002, 23, 324-330. 

Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer s disease progress and problems on the road to therapeutics. Science 297 353—356 Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, CUenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 277 432-438... 

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006) Amyloid-beta vaccination testing the amyloid hypothesis heads we win, tails you lose Am J Pathol 169 738-739... 

Putative Drug T argets in Alzheimer Disease and Amyloid Hypothesis... 

To date, there is no generally accepted theory that accounts for the development of AD pathology. The multifactorial basis of the disease makes such a theory unlikely to be possible in the foreseeable future. In addition to the NFTs and amyloid-hypothesis of the disease, oxidative stress, systemic levels of redox active metal ions, cardiovascular disease, the apoEe4 allele and type 2 diabetes are all clear risk factors for development of AD. However, recent research supports the notion that the Ap buildup may be a key event in AD and that other manifestations of the disease, like NFT formation, result from an imbalance between AP production and AP clearance (17). 

As with any medically driven scientific hypothesis, the ultimate value of the amyloid hypothesis is directly proportional to its clinical utility. A myriad of scientific achievements have occurred since George Glenner first identified the A/3 peptide in amyloidotic vessels in 1984 (150). Biochemical prowess combined with elegant genetics and careful neuropathological analyses have advanced the field to a point where there are numerous anti-amyloid molecules undergoing, or close to, therapeutic evaluation in AD patients. 

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