{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:40:26Z","timestamp":1791668426095,"version":"4.3.4"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R33AG068887"],"award-info":[{"award-number":["R33AG068887"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mitochondrial dysfunction is a hallmark of Alzheimer\u2019s disease, but the scope and severity of these specific deficits across forms of Alzheimer\u2019s disease are not well characterized. We designed a high-throughput longitudinal phenotypic assay to track mitochondrial dynamics and bioenergetics in glutamatergic induced pluripotent stem cell (iPSC)-derived human neurons possessing mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and the amyloid beta precursor protein (APP).<\/jats:p>\n               <jats:p>Each gene set was composed of iPSC-derived neurons from an Alzheimer\u2019s disease patient in addition to two to three engineered mutations with appropriate isogenic and age-matched controls. These iPSC-derived neurons were imaged every other day, beginning at 10 days in vitro, to assess how mitochondrial length and content change over a 10 day time course using a mitochondrially targeted reporter. A second cytosolic reporter allowed for visualization of neurites. Bioenergetics assays, focusing on mitochondrial respiration and individual electron transport chain complexes, were also surveyed over this time course.<\/jats:p>\n               <jats:p>Mutations in all three genes altered mitochondrial function measured by basal, ATP-linked and maximal oxygen consumption rates and by spare respiratory capacity, with PSEN1\/PSEN2 alleles being more severe than APP mutations. Electron flow through Complexes I\u2013IV was decreased in PSEN1\/PSEN2 mutations but, in contrast, APP alleles had only modest impairments of complexes I and II. We measured aspects of mitochondrial dynamics, including fragmentation and neurite degeneration, both of which were dramatic in PSEN1\/PSEN2 alleles, but essentially absent in APP alleles. The marked differences in mitochondrial pathology might occur from the distinct ways in which amyloids are processed into amyloid beta peptides and might be correlated with the disease severity.<\/jats:p>","DOI":"10.1093\/brain\/awae364","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T14:08:43Z","timestamp":1731074923000},"page":"1405-1420","source":"Crossref","is-referenced-by-count":13,"title":["Mitochondrial dynamics and bioenergetics in Alzheimer\u2019s induced pluripotent stem cell-derived neurons"],"prefix":"10.1093","volume":"148","author":[{"given":"Courtney","family":"MacMullen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelam","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald L","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology , Jupiter, FL 33458 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"2025062420051919900_awae364-B1","first-page":"34","article-title":"Early-onset Alzheimer disease and its variants","volume":"25","author":"Mendez","year":"2019","journal-title":"Continuum (Minneap Minn)"},{"key":"2025062420051919900_awae364-B2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cell.2017.07.004","article-title":"Alzheimer\u2019s-causing mutations shift A\u03b2 length by destabilizing \u03b3-secretase-A\u03b2n 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