Neuropathological and Functional Impact of Astrocyte-Derived Extracellular Vesicles in an Aged Model of Alzheimer's Disease

Extracellular vesicles (EVs) are lipid-bound particles that transfer cargos between cells. While plasma neuronal-derived EVs (NEVs) from individuals with mild cognitive impairment (MCI) and Alzheimers disease (AD) have been reported to exhibit high pathogenic potential, this study examined the impact of astrocyte-derived EVs (AEVs) in an aged AD mouse model. Plasma AEVs were isolated from cognitively normal control (CNC), MCI, and AD individuals using GLAST-based immunocapture and AEV size, purity, and tetraspanin were validated by flow cytometry, nanoparticle tracking, and super-resolution microscopy. AEVs pooled by clinical cohort were injected into the hippocampus of 6-month-old female PSAPP mice. Behavioral, biochemical, and neuropathological outcomes were assessed 6 months later. Rotarod assessment revealed significant impairment in motor coordination (p<0.0001) in mice receiving MCI- and AD-AEVs compared with those receiving CNC-AEVs. Morris water maze (MWM) also demonstrated cognitive deficits in MCI- and AD-AEV injected mice; however, no overt changes were observed in the staining of amyloid plaque burden (6E10), and neuroinflammation (GFAP). Immunoblotting of 82E1 and 22C11 confirmed A{beta}/AAP levels remained similar across all injected mice, whereas increased cortical tau accumulation was observed in MCI- and AD-AEV injected mice. Cerebellar synaptic density (SY-38) remained unchanged. While plasma AEVs from healthy individuals may confer neuroprotective benefits, AEVs from cognitively impaired individuals promoted tau accumulation in an amyloidogenic mouse model. These findings suggest that AEVs may play a dual role in AD as both potential biomarkers and mechanistic drivers of neurodegeneration, highlighting their relevance as targets for future therapeutic strategies.