Alzheimer's disease-specific extracellular vesicles: from pathology to novel biomarker discovery

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ABSTRACT Alzheimer’s disease (AD) is one of the most devastating neurological diseases characterized by progressive cognitive impairments, including memory loss. The mechanisms of disease progression are not yet fully elucidated, and to date there are no reliable biomarkers for early detection of pathogenic components. Improved capabilities to assess central nervous system brain health with peripheral biofluid samples (Liquid Biopsy) will expand clinical options at all stages of disease. Extracellular vesicles (EVs) of brain origin (bdEVs) cross biological barriers and can be traced back to specific parent cell types suggesting novel diagnostic, prognostic, and monitoring tools, revolutionizing identification and care of AD as well as understanding pathogenesis. bdEVs carry cargos involved in neurotransmission or neuroprotection and facilitate communication between brain cells also making them “targetable agents” of pathology. To lay the groundwork for more efficient peripheral bdEV studies, we have compared the protein content of brain homogenates with purified EV fractions of control and late-stage AD brains. Proteome differences were most pronounced in EVs, while certain cells release more EVs or EVs with higher density of cell-specific surface markers. Based on these novel findings, we propose to use human induced pluripotent stem cell (hiPSC) models of neurons, astrocytes and microglia to test the specificity and sensitivity of the top CNS surface markers we identified in our preliminary studies as enriched on bdEVs from different cell types and as more abundant in AD patients versus controls (Aim 1). To investigate aging- and neurodegeneration-related proteins and RNAs that were differentially regulated in AD bdEVs, we will study three different sources of EVs, including iPSC-derived progeny (Aim 1), brain tissue (Aim 2), and plasma (Aim 3). We will use the same sources to discover new molecular signatures for disease detection and monitoring.