Neuronal and Astrocytic Extracellular Vesicle Biomarkers in Blood Reflect Brain Pathology in Mouse Models of Alzheimer’s Disease

Abstract

Circulating neuronal extracellular vesicles (NEVs) of Alzheimer’s disease (AD) patients show high Tau and β-amyloid (Aβ) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. To validate EV proteins as AD biomarkers, we immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels. NEVs from 3xTg-AD mice had higher total Tau (p = 0.03) and p181-Tau (p = 0.0004) compared to WT mice. There were moderately strong correlations between biomarkers in NEVs and cerebral cortex and hippocampus (total Tau: cortex, r = 0.4, p = 0.009; p181-Tau: cortex, r = 0.7, p p p p = 0.001) and hippocampus (r = 0.7, p p = 0.005); AEV C1q had moderate-strong correlations with C1q in cortex (r = 0.9, p p < 0.0001). Biomarkers in circulating NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as a “liquid biopsy” for neurological disorders.

Keywords

• extracellular vesicles
• exosomes
• Alzheimer’s
• transgenic
• biomarkers
• Tau