{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:12:07Z","timestamp":1785161527170,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,23]]},"group-title":"Neuroscience","reference-count":79,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01AG078299"],"award-info":[{"award-number":["R01AG078299"]}]},{"name":"NIH","award":["R01AG084624"],"award-info":[{"award-number":["R01AG084624"]}]},{"name":"NIH","award":["R01AG083941"],"award-info":[{"award-number":["R01AG083941"]}]},{"name":"NIH","award":["S10OD030269"],"award-info":[{"award-number":["S10OD030269"]}]},{"name":"NIH","award":["S10OD026983"],"award-info":[{"award-number":["S10OD026983"]}]},{"name":"Spivack Neuroscience Pilot Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Alzheimer\u2019s disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (A\u03b2) pathology, and ameliorated the defects in synaptic marker expression in App\n                  <jats:sup>NL-G-F<\/jats:sup>\n                  AD model mice. Mechanistically, miR-223 induced microglial clustering around A\u03b2 plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene\n                  <jats:italic>SPPL2A<\/jats:italic>\n                  , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.\n                <\/jats:p>","DOI":"10.64898\/2026.07.20.738977","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:40:15Z","timestamp":1784889615000},"source":"Crossref","is-referenced-by-count":0,"title":["MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Andre","family":"Krunic","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA"},{"name":"Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, 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