{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:42:31Z","timestamp":1790840551938,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018378","name":"Owens Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018378","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (A\u03b2) oligomer (xcA\u03b2O) buildup are some well\u2010known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcA\u03b2Os inhibit nutrient\u2010induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock\u2010in (APP<jats:sup>SAA<\/jats:sup>) mice using two\u2010photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>NiMA is inhibited in APP<jats:sup>SAA<\/jats:sup> mice before other defects are detected in these A\u03b2\u2010producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3\u03b2) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3\u03b2 with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP<jats:sup>SAA<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APP<jats:sup>SAA<\/jats:sup> mice, and may represent an early stage in human AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Amyloid beta blocks communication between lysosomes and mitochondria in vivo.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Nutrient\u2010induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock\u2010in (APP<jats:sup>SAA\/+<\/jats:sup>) mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>NiMA is disrupted long before learning and memory deficits in APP<jats:sup>SAA\/+<\/jats:sup> mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Pharmacological interventions can rescue AD\u2010related NiMA disruption in vivo.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.14144","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T13:29:06Z","timestamp":1724333346000},"page":"6844-6859","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP<sup>SAA<\/sup> knock\u2010in mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-1709","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Norambuena","sequence":"first","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay Kumar","family":"Sagar","sequence":"additional","affiliation":[{"name":"Department of Biology University of Virginia  Charlottesville Virginia USA"},{"name":"W.M. 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