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Anti\u2010inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)\u2010derived neural stem cells (NSCs) hold promise as a disease\u2010modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC\u2010NSC\u2010EVs in 3\u2010month\u2010old 5xFAD mice. IN administered hiPSC\u2010NSC\u2010EVs incorporated into microglia, including plaque\u2010associated microglia, and encountered astrocyte soma and processes in the brain. Single\u2010cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease\u2010associated microglia, NOD\u2010, LRR\u2010, and pyrin domain\u2010containing protein 3 (NLRP3)\u2010inflammasome and interferon\u20101 (IFN\u20101) signalling displayed reduced expression in microglia. Adding hiPSC\u2010NSC\u2010EVs to cultured human microglia challenged with amyloid\u2010beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN\u20101 and interleukin\u20106 signalling. Furthermore, the modulatory effects of hiPSC\u2010NSC\u2010EVs on microglia in the hippocampus persisted 2 months post\u2010EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and\/or proteins involved in the activation of p38\/mitogen\u2010activated protein kinase and IFN\u20101 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid\u2010beta plaques, and p\u2010tau were also reduced in the hippocampus. Such modulatory effects of hiPSC\u2010NSC\u2010EVs also led to better cognitive and mood function. Thus, early hiPSC\u2010NSC\u2010EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid\u2010beta plaque load, and p\u2010tau. These results reflect the first demonstration of the efficacy of hiPSC\u2010NSC\u2010EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.<\/jats:p>","DOI":"10.1002\/jev2.12519","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T08:19:53Z","timestamp":1730794793000},"source":"Crossref","is-referenced-by-count":65,"title":["Extracellular vesicles from human\u2010induced pluripotent stem cell\u2010derived neural stem cells alleviate proinflammatory cascades within disease\u2010associated microglia in Alzheimer's disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Leelavathi N.","family":"Madhu","sequence":"first","affiliation":[{"name":"Institute for Regenerative Medicine, Department of Cell Biology and Genetics, College of Medicine Texas A&amp;M University Health Science Center, College Station  Texas 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