Neuronal Membranes are Key to the Pathogenesis of Alzheimer's Disease: the Role of Both Raft and Non-Raft Membrane Domains

Membrane rafts are sterol-and sphingolipid-enriched domains that compartmentalize cellular processes. Membrane rafts isolated from post-mortem AD brain are enriched in both beta-amyloid and phosphorylated tau. Proteolytic processing of APP to generate beta-amyloid, the principle component of amyloid plaques, can occur in membrane rafts, implicating them in the pathogenesis of Alzheimer's disease ( AD). Secondary to their role in beta-amyloid generation, membrane rafts have more recently been implicated in the accumulation, aggregation and degradation of beta-amyloid, with evidence supporting a specific role for membrane raft gangliosides in the binding and aggregation of beta-amyloid. In addition, membrane domain composition has a direct impact on both the generation of beta-amyloid and its subsequent toxic actions and as such is a key target for the development of therapeutic strategies. This mini-review will focus on recent advances in our understanding of the relevance of membrane composition, of both raft and non-raft domains, to AD progression in models and in human disease. We will discuss how manipulation of membrane composition can alter both the proteolytic processing of APP and the subsequent binding and aggregation of beta-amyloid peptide.