Presence of soluble amyloid β–peptide precedes amyloid plaque formation in Down's syndrome

Abstract

Abnormal and excessive accumulation of the amyloid β–peptide (Aβ) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of Aβ are identified as amyloid plaques. These deposits are thought to form when the amount of Aβ is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP)^1–3. Soluble Aβ ending at carboxyl–terminal residue 40 (Aβ₄₀) and, in lesser amount, the form ending at residue 42 (Aβ₄₂), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble Aβ₄₂ has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble Aβ₄₂ plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages^6,7. Moreover, it has been observed that Aβ₄₂ precedes Aβ₄₀ in the course of amyloid deposition in DS brain⁸. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble Aβ₄₂ is present in the brains of DS–affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age–matched controls. It is argued that overexpression of APP leads specifically to Aβ₄₂ increase and that the presence of the soluble Aβ₄₂ is causally related to plaque formation in DS and, likely, in AD brains.