ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer's disease

Despite the various mechanisms that involved in the pathogenesis of Alzheimer's disease (AD), neuronal damage and synaptic dysfunction are the key events leading to cognition impairment. Therefore, neuroprotection and neurogenesis would provide essential alternatives to the rescue of AD cognitive function. Here we demonstrated that extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs-derived EVs, abbreviated as EVs) entered the brain quickly and efficiently following intranasal administration, and majorly accumulated in neurons within the central nervous system (CNS). Proteomics analysis showed that EVs contained multiple proteins possessing neuroprotective and neurogenesis activities, and neuronal RNA sequencing showed genes enrichment in neuroprotection and neurogenesis following the treatment with EVs. As a result, EVs exerted powerful neuroprotective effect on Aβ_1-42 oligomer or glutamate-induced neuronal toxicity, effectively ameliorated neurologic damage in the whole brain areas, remarkably increased newborn neurons and powerfully rescued memory deficits in APP/PS1 transgenic mice. EVs also reduced Aβ deposition and decreased microglia activation although in a less extent. Collectively, here we provide direct evidence that ADSCs-derived EVs may potentially serve as an alternative for AD therapy through alleviating neuronal damage and promoting neurogenesis.