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-beta (Abeta) peptide aggregates in the brain of affected individuals. Abeta is derived from a type I transmembrane protein, amyloid precursor protein (APP), by the sequential proteolytic events mediated by beta-site APP cleaving enzyme 1 (BACE1) and gamma-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, beta- and gamma-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.

Fig. 1

Schematic illustration of intracellular itinerary of amyloid precursor protein (APP). Synthetic APP is trafficked through the constitutive secretory pathway to the plasma membrane (blue arrows). From the cell surface, a fraction of APP is internalized and trafficked through endocytic and recycling compartments (red arrows) to reach the cell surface, the TGN, or sorted to the lysosomes for degradation (dotted red arrows). Non-amyloidogenic processing occurs mainly at the cell surface, where α-secretase activity is abundant. Amyloidogenic processing likely occurs in the endocytic pathway as APP encounters BACE1 and γ-secretase in the endosomes and recycling organelles. γ-secretase subunits and APP CTFs are enriched in lipid raft microdomains isolated from these compartments (highlighted by a circle). EE, Early endosome; For simplicity, the constitutive secretory trafficking pathway is not indicated by arrows.

Fig. 2

Raft targeting signals identified in BACE1 and γ-secretase subunits nicastrin and APH1. BACE1 is S-palmitoylated at four Cys residues (Cys474/478/482/485) located at transmembrane and cytoplasmic boundary. (B) S-palmitoylation of γ-secretase subunits nicastrin and APH1 at indicated Cys residues were identified by mutagenesis; Nicastrin is S-palmitoylated at Cys 689 and APH1 is at Cys 182/245.