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Our previous research demonstrated the neuroprotective benefits of human neural stem cell (hNSC)\u2010derived EVs in 2\u2010 and 6\u2010month\u2010old AD mice (5xFAD) that exibited improved cognitive function and reduced AD\u2010related neuropathology. This study aimed to compare the neuroprotective efficacy of EVs derived from two human cell lines: hNSCs from H9 embryonic stem cells and human iPSC\u2010derived microglia (iMGLs). Additionally, we investigated the efficacy of an expanded EV treatment paradigm at subsequently longer time points. Three\u2010month\u2010old 5xFAD mice received weekly retro\u2010orbital vein injections of either hNSC\u2010 or iMGL\u2010derived EVs for 4\u2009weeks. Cognitive function testing revealed comparable cognitive improvements in both EV treatment groups compared to vehicle\u2010injected AD mice. Both iMGL\u2010 and hNSC\u2010derived EVs significantly reduced amyloid beta plaques, astrogliosis, and microglial activation, while restoring synaptophysin and postsynaptic density protein PSD\u201095 to control levels in AD brains. Gene expression analysis revealed significantly reduced neuroinflammation and elevated neuroprotective signatures following both EV treatments. MicroRNA analysis of the EV\u2010derived cargo revealed unique and shared miRNA signatures associated with differentially expressed genes in both cell lines. These findings demonstrate the feasibility and neuroprotective benefits of recurrent systemic injections of EVs derived from human NSCs and differentiated human microglia lines in alleviating cognitive dysfunction and neuropathology in Alzheimer's disease.<\/jats:p>","DOI":"10.1111\/acel.70341","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T13:11:31Z","timestamp":1766495491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Comparing Functional Consequences of Human\n                    <scp>iPSC<\/scp>\n                    \u2010Microglia and Neural Stem Cell\u2010Derived Extracellular Vesicles in Mitigating Cognitive Decline in Alzheimer's Disease"],"prefix":"10.1111","volume":"25","author":[{"suffix":"Jr.","given":"Robert P.","family":"Krattli","sequence":"first","affiliation":[{"name":"Department of Anatomy &amp; Neurobiology University of California Irvine  Irvine 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