Membrane rafts in Alzheimer's disease beta-amyloid production

Abstract

Alzheimer's disease (AD), the most common age-associated dementing disorder, is pathologically manifested by progressive cognitive dysfunction concomitant with the accumulation of senile plaques consisting of amyloid-β (Aβ) peptide aggregates in the brain of affected individuals. Aβ is derived from a type I transmembrane protein, amyloid precursor protein (APP), by the sequential proteolytic events mediated by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Multiple lines of evidence have implicated cholesterol and cholesterol-rich membrane microdomains, termed lipid rafts in the amyloidogenic processing of APP. In this review, we summarize the cell biology of APP, β- and γ-secretases and the data on their association with lipid rafts. Then, we will discuss potential raft targeting signals identified in the secretases and their importance on amyloidogenic processing of APP.

Introduction

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that is predominant among aged individuals. The principal pathological hall marks of AD, originally described by Alois Alzheimer a little over one hundred years ago, are the two lesions, neurofibrillary tangles and senile plaques, which are found at significantly higher frequency in the cortex and hippocampus in individuals afflicted with AD compared to age matched healthy individuals [1]. Eighty years later, the molecular composition of senile plaques was deciphered with the advent of advanced biochemical and genetic tools. Senile plaques consist of extracellular deposits of 39–42 amino acid-long amyloid-β (Aβ) peptides. Subsequent studies revealed that Aβ is released from a large type I transmembrane protein, termed amyloid precursor protein (APP), by the sequential proteolysis of a set of enzymes termed β- and γ-secretases. Identification of familial AD-linked mutations in APP gene launched the exploration of the cell biology of APP and these secretases to modulate Aβ production to attenuate disease pathology. A growing body of evidence indicates that changes in cholesterol homeostasis can influence Aβ production, and studies in neuronal and non-neuronal cells implicate cholesterol-enriched membrane microdomains, termed lipid rafts, in amyloidogenic processing of APP. However, the connection between cholesterol, lipid rafts and APP processing has not been completely understood, and controversy still exists. In this review, we will first describe the cell biology of APP, β- and γ-secretases followed by the mechanistic details of amyloidogenic processing. Then, we will elaborate on the current status of research addressing the importance of raft association of BACE1 and γ-secretase, and discuss potential raft targeting signals in the secretases and their unanticipated redundant role on amyloidogenic processing of APP.