{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:13:46Z","timestamp":1785420826028,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,20]]},"group-title":"Neuroscience","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R35GM124824"],"award-info":[{"award-number":["R35GM124824"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01NS118014"],"award-info":[{"award-number":["R01NS118014"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1NS134549"],"award-info":[{"award-number":["RF1NS134549"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1NS113820"],"award-info":[{"award-number":["RF1NS113820"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1NS127925"],"award-info":[{"award-number":["RF1NS127925"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG078948"],"award-info":[{"award-number":["R01AG078948"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer\u2019s disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5\u00d7FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of\n                  <jats:italic>Cmpk2<\/jats:italic>\n                  , a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces\n                  <jats:italic>Cmpk2<\/jats:italic>\n                  expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-\u03b2 burden, restore synaptic plasticity, and improve cognitive function in 5\u00d7FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.\n                <\/jats:p>","DOI":"10.64898\/2026.02.19.706884","type":"posted-content","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T20:55:15Z","timestamp":1771620915000},"source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer\u2019s disease pathogenesis"],"prefix":"10.64898","author":[{"given":"Yongqing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Fan","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhi","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry Yi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Solomon H. 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