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 Alzheimer's 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. While Morris water maze (MWM) also demonstrated that CNC-AEVs injected mice exhibited a trend toward increased target quadrant entries and faster escape latencies, these measures did not reach did not reach statistical significance. No overt changes were observed in the staining of amyloid plaque burden (6E10), and astrogliosis (GFAP). Immunoblotting of 82E1 and 22C11 confirmed Aβ/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. These findings suggest that while human-derived AEVs can precipitate early tau-related changes and motor coordination deficits, they do not significantly alter overall amyloidosis or astrocyte-reactivity at this time point. Further investigation is required to determine the viability of AEVs as biomarkers or therapeutic targets given the subtle nature of the observed structural pathology.