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3. GENETIC ASPECTS OF ALZHEIMER'S DISEASE

The Amyloid Hypothesis of Alzheimer's Disease

The following points are made by J. Hardy and D.J. Selkoe (Science 2002 297:353):

1) Amyloid beta-peptide (A-beta), the sticky peptide prominent in the brain plaques characteristic of Alzheimer's disease (AD), was first sequenced from the meningeal blood vessels of AD patients and individuals with Downs syndrome nearly 20 years ago (1,2). A year later, the same peptide was recognized as the primary component of the senile (neuritic) plaques of AD patient brain tissue (3). These discoveries mark the beginning of the modern era of research on this common, devastating neurodegenerative disease.

2) The subsequent cloning of the gene encoding the beta-amyloid precursor protein (APP) and its localization to chromosome 21 (4,5), coupled with the earlier recognition that trisomy 21 (Downs syndrome) leads invariably to the neuropathology of AD, set the stage for the proposal that A-beta accumulation is the primary event in AD pathogenesis. In addition, the identification of mutations in the APP gene that cause hereditary cerebral hemorrhage with amyloidosis (Dutch type) showed that APP mutations could cause A-beta deposition, albeit largely outside the brain parenchyma.

3) Soon, the first genetic mutations causing AD were discovered in the APP gene. The contemporaneous discovery that A-beta was a normal product of APP metabolism throughout life and could be measured in culture medium, cerebrospinal fluid, and plasma allowed researchers to quickly establish the biochemical abnormalities caused by APP mutations. Most of the mutations cluster at or very near the sites within APP that are normally cleaved by proteases called the alpha-, beta-, and gamma-secretases. In accordance with this, these mutations promote generation of A-beta by favoring proteolytic processing of APP by beta- or gamma-secretase. Furthermore, APP mutations internal to the A sequence heighten the self-aggregation of A-beta into amyloid fibrils. These developments provided a genetic framework for the emerging amyloid hypothesis.

4) In the past decade, bolstered particularly by the cloning of the presenilin (PS) proteins and the demonstration that AD-causing mutations in PS1 and PS2 also enhance the processing of APP to form amyloidogenic A-beta, the amyloid hypothesis has become the focus of much AD research.

References (abridged):

1. G. G. Glenner and C. W. Wong, Biochem. Biophys. Res. Commun. 120, 885 (1984)

2. G. G. Glenner and C. W. Wong, Biochem. Biophys. Res. Commun. 122, 1131 (1984)

3. C. L. Masters et al., Proc. Natl. Acad. Sci. U.S.A. 82, 4245 (1985)

4. J. Kang et al., Nature 325, 733 (1987)

5. D. Goldgaber, M. I. Lerman, O. W. McBridge, V. Saffiotti, D. C. Gajdusek, Science 235, 877 (1987)

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