Exosomes as Carriers of Alzheimer's Amyloid-ß

Abstract

The intracerebral level of the aggregation-prone peptide, amyloid-ß (Aß), is constantly maintained by multiple clearance mechanisms, including several degradation enzymes, and brain efflux. Disruption of the clearance machinery and the resultant Aß accumulation gives rise to neurotoxic assemblies, leading to the pathogenesis of Alzheimer's disease (AD). In addition to the classic mechanisms of Aß clearance, the protein may be processed by secreted vesicles, although this possibility has not been extensively investigated. We showed that neuronal exosomes, a subtype of extracellular nanovesicles, enwrap, or trap Aß and transport it into microglia for degradation. Here, we review Aß sequestration and elimination by exosomes, and discuss how this clearance machinery might contribute to AD pathogenesis and how it might be exploited for effective AD therapy.

Keywords: Alzheimer's disease; amyloid-ß; exosome; glycosphingolipid; microglia.

Figure 1

Pathway of exosome-dependent Aß clearance. APP is sorted into endosomes with acidic pH, where it is sequentially cleaved by secretases to produce Aß. The resultant Aß is released to the extracellular milieu through fusion of recycling endosomes or MVBs with the plasma membrane. Some Aß is associated with exosomes in MVBs or in the extracellular space, an interaction mediated by GSLs. Exosomes stack Aß on their surface by promoting the formation of nontoxic Aß assembly by GSLs, followed by incorporation of Aß fibrils into microglia in a PS-dependent manner, resulting in degradation. Thus, neuronal exosomes are likely to promote Aß clearance. In absence of microglial phagocytic activity, exosome-associated Aß might induce any pathogenic event, such as amyloid plaque formation.