{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:08:49Z","timestamp":1788908929211,"version":"build-2803163510"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Neurodegener"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-\u03b2 (A\u03b2) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3\u2009\u00d7\u2009Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9\u00a0months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal A\u03b2 levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3\u2009\u00d7\u2009Tg-AD mice and reduced hippocampal A\u03b2 levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3\u2009\u00d7\u2009Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00581-1","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:02:03Z","timestamp":1788908523000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"15","author":[{"given":"Andrea","family":"Papait","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Natale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta Rosa","family":"Silini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Nifo Sarrapochiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Orecchini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimondo","family":"Sollazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Rinaudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serafina","family":"Farigu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Garofalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Mantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido Maria","family":"Giuffr\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Romele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Ragozzino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Dellaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Giac\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camillo","family":"Marra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Ripoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-1685","authenticated-orcid":false,"given":"Claudio","family":"Grassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Parolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Fusco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"s1","key":"581_CR1","doi-asserted-by":"publisher","first-page":"S51","DOI":"10.3233\/JAD-201059","volume":"82","author":"L Guzman-Martinez","year":"2021","unstructured":"Guzman-Martinez L, Calf\u00edo C, Farias GA, Vilches C, Prieto R, Maccioni RB. 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All procedures involving human samples were conducted in accordance with the principles of the Declaration of Helsinki. Human term placentas were obtained from healthy donors following vaginal delivery or cesarean section after written informed consent was provided. The protocol was approved by the local Institutional Ethics Committee [Comitato Etico Provinciale di Brescia, Italy; approval number NP 2243, January 19, 2016]. Skin biopsies (to generate iPSC-derived neurons) were collected from the perimalleolar region of three individuals diagnosed with sporadic Alzheimer\u2019s disease and three healthy subjects at the Clinics of Memory of Fondazione Policlinico Universitario A. Gemelli IRCCS after written informed consent was provided. The protocol was approved by the local Institutional Ethics Committee (NP 0005057\/23, February 16, 2023).","order":3,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"46"}}