FIBRILLOGENESIS IN ALZHEIMERS-DISEASE OF AMYLOID-BETA PEPTIDES AND APOLIPOPROTEIN-E

A central event in Alzheimer's disease is the conformational change fr om normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neur ofibrillary tangles respectively. The apolipoprotein E (apoE) gent loc us has recently been associated with late-onset Alzheimer's disease. I t is not known whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE ca n affect the known spontaneous in vitro formation of amyloid-like fibr ils by synthetic A beta analogues using a thioflavine-T assay for fibr il formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid f ibril formation, increasing both the rate of fibrillogenesis and the t otal amount of amyloid formed. ApoE accelerated fibril formation of bo th wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone prod uces few amyloid-like fibrils. However, apoE produced only a minimal e ffect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's dis ease. When recombinant apoE isoforms were used, apoE4 was more efficie nt than apoE3 at enhancing amyloid formation. These in vitro observati ons support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.