The role of cerebral amyloid β accumulation in common forms of Alzheimer disease
Sam Gandy
Sam Gandy
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Science in Medicine

The role of cerebral amyloid β accumulation in common forms of Alzheimer disease

Abstract

For approximately 80 years following Alzheimer’s description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

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Sam Gandy

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Figure 7

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APOE isoform–specific regulation of Aβ plaque burden. Aβ plaque load is ...
APOE isoform–specific regulation of Aβ plaque burden. Aβ plaque load is highest in the hippocampi of mice expressing murine apoE (A, magnified in B) and lowest in APOE knockout animals (C, magnified in D). Plaque load is moderate in the hippocampi of human APOE ε4–expressing mice (E, magnified in F) as compared to murine apoE–expressing mice. Plaque load in the hippocampi of human APOE ε4–expressing mice is greater than plaque load in the hippocampi from human APOE ε3–expressing mice (G, magnified in H). Amyloid deposits in the dentate gyrus, indicated by arrows, never develop in the absence of apoE. Scale bar: 150 μm (A, C, E, and G) and 60 μm (B, D, F, and H). Figure modified with permission from Proceedings of the National Academy of Sciences of the United States of America (40).