DAMAGED LIPID RAFTS AT THE EARLIEST STAGES OF ALZHEIMER’S DISEASE: IMPLICATIONS IN AMYLOIDOGENIC PROCESSING

Abstract

The existence of lipid alterations in lipid rafts from human frontal cortex in late stages of Alzheimer's disease (AD) has been demonstrated, however, little is known about the early onset of these biochemical aberrations. We have isolated and analysed the lipid composition of lipid rafts from human brain areas from AD at different neuropathological stages and age-matched controls. Lipid rafts from frontal and entorhinal cortices are profoundly altered in AD brains at initial stages of AD (AD I/II and AD III/IV). Changes in the lipid matrix affected both lipid classes and fatty acids in cortical lipid rafts, but not in the cerebellum, from the same subjects. Lipid alterations were paralleled by increased membrane order, microviscosity, and accumulation of BACE (β-secretase) and APP (Amyloid Precursor Protein) within lipid rafts in AD subjects even at the earliest stages. Our results disclose a physicochemical association between lipid alterations in lipid rafts microdomains and the amyloidogenic processing of APP.