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How neuronal ABCA7 contributes to AD pathogenesis is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n Using neuron\u2010specific\n Abca7<\/jats:italic>\n KO mice (n\n Abca7<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ) with or without 5\u00d7FAD amyloid model background and\n post mortem<\/jats:italic>\n AD brains, we investigated AD\u2010related phenotypes through comprehensive approaches including transcriptomics and lipidomics.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5\u00d7FAD; n\n Abca7<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5\u00d7FAD; n\n Abca7<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n Neuronal ABCA7 deficiency exacerbates A\u03b2 pathology and neuronal damage in 5\u00d7FAD mice.<\/jats:p>\n <\/jats:list-item>\n \n Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5\u00d7FAD mice.<\/jats:p>\n <\/jats:list-item>\n \n Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5\u00d7FAD mice.<\/jats:p>\n <\/jats:list-item>\n \n \n Neuronal\n ABCA7<\/jats:italic>\n expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70112","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T23:42:24Z","timestamp":1743291744000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Ni","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neuroscience Mayo Clinic Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Public Health University of North Florida Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skylar 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