Impacts of Membrane Biophysics in Alzheimer's Disease: From Amyloid Precursor Protein Processing to A β Peptide-Induced Membrane Changes

Abstract

An increasing amount of evidence supports the notion that cytotoxic effects of amyloid- β peptide (A β ), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. A β is derived from amyloidogenic cleavage of amyloid precursor protein (A β PP) by β - and γ -secretase. In the nonamyloidogenic pathway, A β PP is cleaved by α -secretases. These two pathways compete with each other, and enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of AD. Since A β PP, α -, β -, and γ -secretases are membrane-associated proteins, A β PP processing and A β production can be affected by the membrane composition and properties. There is evidence that membrane composition and properties, in turn, play a critical role in A β cytotoxicity associated with its conformational changes and aggregation into oligomers and fibrils. Understanding the mechanisms leading to changes in a membrane's biophysical properties and how they affect A β PP processing and A β toxicity should prove to provide new therapeutic strategies for prevention and treatment of AD.