PRESENCE OF SOLUBLE AMYLOID BETA-PEPTIDE PRECEDES AMYLOID PLAQUE-FORMATION IN DOWNS-SYNDROME

Abnormal and excessive accumulation of the amyloid beta-peptide (A bet a) in the brain is a major and common characteristic of all Alzheimer' s disease (AD) forms irrespective of their genetic background. Insolub le aggregates of A beta are identified as amyloid plaques. These depos its are thought to form when the amount of A beta is. increased in the brain parenchyma as a result of either overexpression or altered proc essing of the amyloid precursor protein (APP)(1-3). Soluble A beta end ing at carboxyl-terminal residue 40 (A beta(40)) and, in lesser amount , the form ending at residue 42 (A beta(42)) are normal products of th e APP metabolism in cell cultures. Increased secretion of soluble A be ta(42) 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 s oluble AP, 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 almo st invariably develop amyloid deposits after the age of 30 years, alth ough they are free of them at earlier ages(6,7). Moreover, it has been observed that A beta(42) precedes A beta(40) in the course of amyloid deposition in DS brains. 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 A b eta(42) is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched co ntrols. It is argued that overexpression of APP leads specifically to A beta(42) increase and that the presence of the soluble A beta(42) is causally related to plaque formation in DS and, likely, in AD brains.