Amyloid β-Induced Inflammarafts in Alzheimer's Disease

Abstract

The formation of amyloid beta (Aβ) plaques is a central process in the development of Alzheimer's disease (AD). Although its causative role or the effectiveness of therapeutic targeting is still debated, the key involvement of Aβ in the pathogenesis of neuroinflammation and neurodegeneration in AD is broadly accepted. In this review, we emphasize the role of lipid rafts, both in APP cleavage producing Aβ in neurons and in mediating Aβ inflammatory signaling in microglia. We introduce the term inflammarafts to characterize the Aβ-driven formation of enlarged, cholesterol-rich lipid rafts in activated microglia, which support protein-protein and lipid-protein interactions of inflammatory receptors. Examples reviewed include toll-like receptors (TLR2, TLR4), scavenger receptors (CD36, RAGE), and TREM2. The downstream pathways lead to the production of cytokines and reactive oxygen species, intensifying neuroinflammation and resulting in neuronal injury and cognitive decline. We further summarize emerging therapeutic strategies and emphasize the utility of apolipoprotein A-I binding protein (AIBP) in selective targeting of inflammarafts and attenuation of microglia-driven inflammation. Unlike the targeting of a single inflammatory receptor or a secretase, selective disruption of inflammarafts and preservation of physiological lipid rafts offer a novel approach to targeting multiple components and processes that contribute to neuroinflammation in AD.

Keywords: Alzheimer’s disease; amyloid beta; apolipoprotein A-I binding protein; inflammarafts; inflammation; lipid rafts; microglia; reactive oxygen species.

Figure 1

Amyloid β-induced inflammaraft formation and its therapeutic targeting in Alzheimer’s disease. In neurons, amyloid precursor protein (APP) is processed by β-secretase BACE1 and γ-secretase within lipid rafts to generate amyloid beta (Aβ), which can form oligomers. (1) Aβ oligomers spread, bind to microglial surface receptors and membrane lipids (such as cholesterol and gangliosides), and promote the formation of enlarged, cholesterol-rich microdomains termed inflammarafts. Inflammarafts are the membrane platforms for TLR4 dimerization, the assembly of CD36-TLR heterodimers (CD36-TLR4/6 and CD36-TLR2/1), RAGE dimerization, and the formation of TREM2-DAP12 signaling complexes. (2) Activated microglia subsequently release pro-inflammatory cytokines and reactive oxygen species (ROS), which propagate inflammatory signaling and oxidative stress in surrounding neurons, contributing to neurodegeneration.