Hippocampal administration of astrocyte‐derived extracellular vesicles (AEVs) exacerbates motor deficits and impairs spatial memory in a mouse model of Alzheimer’s Disease

Abstract Background Understanding the therapeutic and/or pathogenic potential of extracellular vesicles (EVs) and their cargo has emerged as an important topic in relation to development of Alzheimer’s disease (AD) and other age‐related dementias (ADRD). Here, we tested the impact of treatment of astrocyte‐derived plasma EVs on cellular and functional recovery was explored in aged, AD (PSAPP) mice. Method Plasma EVs derived from normal controls, mild cognitively impaired (MCI), and AD subjects (n = 7 = /group) were extracted, precipitated using a polymer‐based isolation method (ExoQuick), and enriched against an astrocyte (GLAST) source using magnetic immunocapture and fluorescence‐activated cell sorting. Pooled AEV preparations were injected unilaterally into the right hippocampus of 7m old, female, PSAPP mice. AD‐related neuropathological changes and functional deficits in spatial learning and memory (Morris Water Maze), gait stability (rotarod) and anxiety (SLMA) were assessed at 7 months post injection (mpi). Result We observed MCI and AD AEV injected mice took a longer time and traveled a shorter distance to reach the cued and hidden platform as compared to mice injected with AEVs from normal controls. After the platform was removed, we observed MCI and AD AEV injected mice made significantly fewer entries into the correct quadrant zone and fewer entries into the correct target zone where the platform was originally located. Motor function was significantly impaired in MCI and AD AEV injected mice as compared to control AEV injected mice. Behavioral impairments correlated with increased gliosis, as measured by Iba1 and GFAP, and increased plaque burden, as measured by 6E10 antibody, in the brains of MCI and AD AEV injected mice. Similar levels of phosphorylated tau immunoreactivity were observed in all three mice groups. Conclusion AEVs derived from cognitively impaired subjects transfer toxic proteins to hippocampal cells and exacerbate functional impairments and AD neuropathology in vivo. Cellular and functional recovery was observed in mice injected with EVs from control subjects.