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New clues to the understanding of Alzheimer's: gateways for future research

A recently discovered glycoprotein, amyloid beta protein precursor (APP), is believed to play a vital role in the pathogenesis of Alzheimer's disease (AD). An "" 40-amino acid peptide fragment of this macromolecule, amyloid beta protein (AfJP), is the main proteinaceous component of extracellular deposits isolated from postmortem brain tissue of patients with AD. This deposition of amyloid protein may be the cause, or the result, of nerve degeneration. If the former holds true, elucidation of the mechanism of amyloid deposition and accumulation may be the key to understanding the pathogenesis of AD and may provide insight for the development of future therapies.

APP is encoded by a gene found on chromosome 21. Under normal conditions it is cleaved by APP secretase within the AfJP peptide sequence. However, an alternative catabolic pathway leads to release of intact AfJP peptides. Diffuse AfJP deposits have been isolated from younger subjects with Down's syndrome (trisomy 21), who tend to develop senile plaques indistinguishable from those of AD if they survive to > 40 years of age. A genetic link between AD and Down's syndrome appears feasible. However, in Down's syndrome it is believed that duplication of a structurally normal gene leads to increased transcription of APP, and that excess APP molecules are diverted to the alternative catabolic pathway with resultant acceleration of AfJP formation and early beta amyloid deposition. No such defect in the APP coding region of chromosome 21 has been found in AD. Also, as there is no genetic linkage between familial AD and the APP gene, the APP gene does not appear to be the site of the inherited defect. Perhaps inefficient APP secretase activity is the key etiological event in AD, and attempts to potentiate the activity of this enzyme may be a starting point for therapeutic research.

An AfJP-like protein has also been isolated

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from meningeal and cerebral vessel amyloid deposits in patients with the rare disease. autosomal dominant hereditary cerebral baemorrhage with amyloidosis of the Dutch type (HCHWA-D). In addition, cortical deposits in HCHWA-D resemble the diffuse plaques of AD. Thus, 2 clinically distinct brain disorders may be pathogeneticall y related . A mutation of the common ancestral allele of APP has been proposed as the primary defect in HCHW A-D. This mutation may alter the binding of APP .secretase. allowing conversion of some APP molecules to A{:iP by the alternative pathway. A mutation of A{:iP itself may also be implicated. These findings may also be applicable to AD.

AiJP-immunoreactive deposits have recently been found in the skin and intestine of AD and

aged non-AD subjects, predominantly in and around blood vessels. Thus, some of the AfJP accumulating in AD and aging could be of vascular or circulating origin, in contrast to the general view that neurons are the most likely source of A{:iP deposition. Further study is required to elucidate the origin of AfJP.

Although a number of questions remain unanswered. it seems likely that A{:i P deposition is a vital early pathogenetic event in AD. Until further discoveries are made. study of beta amvloidosis is the most logical starting point for fut~lre research into the development of therapeutic modalities for the prevention and treatment of this currently un treatable disease.

ISSN 0156-2703/ 90/ 0825-0002/ 0$01.00/0 © Adis International ~