The amyloid cascade hypothesis

In 1984, the protein deposited in blood vessels (congophilic angiopathy) in AD was shown to be a 4-kDa peptide known as b-amyloid. (45> This peptide, which is identical to the amyloid in plaques, is derived from a larger peptide, APP, the gene for which is coded on chromosome 21. After a series of misleading linkage studies, mutations in the APP gene were found in a family with autosomal dominant early-onset AD.(46) These two discoveries—the identification of b-amyloid and the discovery of mutations in the parent APP gene—led the way to the amyloid cascade hypothesis, which has remained the dominant molecular model of the disorder. (47> Many subsequent molecular observations have been consistent with this model, which posits the formation of b-amyloid as the initiating, or at least early event, leading to all the other changes observed including tau aggregation and phosphorylation, neuronal loss, cholinergic deficits, and clinical symptoms. Perhaps the most convincing evidence that there is such a unidirectional cascade comes from the observation that mutations in the APP gene give rise to plaque formation and also to neurofibrillary tangle pathology, whereas mutations in the tau gene give rise to tangle formation but not to plaque formation in FTDP-17.

Much subsequent research has concentrated upon understanding the metabolism of APP and the formation of b-amyloid peptide.(4 ,49> APP is a ubiquitous single-pass cell-membrane protein expressed in many cell lines with a high degree of evolutionary conservation. At least three putative secretases cleave APP and the metabolic products can be detected in individuals unaffected by AD; the processing is not pathological in AD, but the balance between different metabolic routes may be shifted in the disease state. a-Secretase cleaves APP at the outer cell-membrane surface at a site within the b-amyloid moiety itself. Clearly, a-secretase cannot therefore yield intact b-amyloid, and this metabolic route, resulting in a secreted product, APPs, and other fragments, is termed non-amyloidogenic. a-Secretase activity is increased following stimulation of protein kinase C. (50) This might have some clinical relevance as certain neuronal receptors are coupled to protein kinase C and, indeed, muscarinic agonists do increase non-amyloidogenic metabolism. These studies predict that therapies designed to correct the cholinergic deficit in AD might have a disease modification effect.(51)

Amyloidogenic metabolism is the result of b-secretase cleaving APP beyond the amino terminus of b-amyloid and of g-secretase cleaving the resulting peptides at the carboxy terminus in the cell. The b-amyloid products vary in length, with predominant species having a length of 40 or 43 amino acids. The longer peptides are somewhat more prone to forming fibrils in vitro. It is probable that the proportion of b-amyloid(42 and 43) peptides relative to b-amyloid(40) peptides is critical in pathogenesis,(49) and that mutations in the APP gene increase these longer amyloid peptides.(52,53) Transgenic mice overexpressing the mutated APP gene also produce more b-amyloid peptide and have amyloid deposits in brain.(54) Interestingly, these animals do not develop other aspects of AD pathology.

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