Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and a leading cause of dementia. Although the amyloid-β (Aβ) peptide is deemed a crucial driver of AD, there are no effective therapeutics available to treat Aβ-caused neurotoxicity. Exosomes are extracellular vesicles with a size range of 30 – 150 nanometers in diameter. Stem cell-derived exosomes are a potential therapeutic in AD, while exosomes isolated from normal stem cell cultures generally have a low yield. Here, we studied the exosomes secreted by the rat neural stem cells in the presence of heat shock (HS) stimulus. Nanoparticle tracking analysis confirmed HS-derived exosomes exhibit significantly higher concentration and larger diameter in comparison to the non-heat shock (NHS)-derived exosomes. Mass spectrometric studies of exosomal proteins reveal that HS-derived exosomes contained fewer diverse proteins than NHS-derived exosomes. GO enrichment analysis of the proteins suggested that the top two biological functions of the proteins in HS-derived exosomes are involved in the negative regulation of apoptotic process and positive modulation of DNA repair. Importantly, the therapeutic efficacy of the NHS- and HS-derived exosomes were tested in a cell culture model of AD: HS-derived exosomes exhibited greater neuroprotection against not only oxidative stress but also amyloid-β (Aβ) induced neurotoxicity compared to NHS-derived exosomes. These data indicate that in response to HS, neural stem cells increase exosome production and alter exosome morphology and cargo to confer better neuroprotection against oxidative stress and Aβ caused neurotoxicity, suggesting that HS-induced exosomes from neural stem cells can be a therapeutic reagent for AD and possibly other neurological disorders.

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