Relationships of Alzheimer’s disease and apolipoprotein E genotypes with small RNA and protein cargo of brain tissue extracellular vesicles

Abstract

ABSTRACTAlzheimer’s disease (AD) is a public health crisis that grows as populations age. Hallmarks of this neurodegenerative disease include aggregation of beta-amyloid peptides and hyperphosphorylated tau proteins in the brain. Variants of the APOE gene are the greatest known risk factors for sporadic AD. As emerging players in AD pathophysiology, extracellular vesicles (EVs) contain proteins, lipids, and RNAs and are involved in disposal of cellular toxins and intercellular communication. AD-related changes in the molecular composition of EVs may contribute to pathophysiology and lend insights into disease mechanisms. We recently adapted a method for separation of brain-derived EVs (bdEVs) from post-mortem tissues. Using this method, we isolated bdEVs from AD patients with different APOE genotypes and controls. bdEVs were counted, sized, and subjected to parallel small RNA sequencing, proteomic analysis. Although overall bdEV concentration was not affected by AD, we observed a shift towards smaller particles in AD. Also, numerous bdEV-associated RNAs (including miRNAs and tRNAs) and proteins were found to be correlated with AD pathology and APOE genotype. Some of the identified entities have been implicated previously in important AD-related pathways, including amyloid processing, neurodegeneration, and metabolic functions, etc. Prominently, AD hallmark Tau and Tau phosphorylated at threonine 231 (phosTau) were significantly increased in AD bdEVs, indicating the involvement of bdEVs in spread of Tau pathology. These findings provide further evidence that bdEVs and their molecular cargo modulate development and progression of AD.