{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:48:56Z","timestamp":1787939336070,"version":"build-2784847793"},"reference-count":39,"publisher":"SAGE Publications","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,9,28]]},"abstract":"<jats:p>Background: Dominant missense mutations in the amyloid-\u03b2 protein precursor (A\u03b2PP) cause early-onset familial Alzheimer\u2019s disease (FAD) and are associated with changes in the production or properties of the amyloid-\u03b2 peptide (A\u03b2), particularly of the 42-residue variant (A\u03b242) that deposits in the Alzheimer\u2019s disease (AD) brain. Recent findings, however, show that FAD mutations in A\u03b2PP also lead to increased production of longer A\u03b2 variants of 45\u201349 residues in length. Objective: We aimed to test neurotoxicity of A\u03b242 vis-\u00e1-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. Methods: We generated SH-SY5Y human neuroblastoma cells stably expressing A\u03b2PP mutations that lead to increased production of long A\u03b2 peptides with or without A\u03b242. These A\u03b2PP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results: The mutant A\u03b2PP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of A\u03b242 production. Moreover, mutant A\u03b2PP-expressing cells producing longer forms of A\u03b2 displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not A\u03b242 was produced. Conclusion: These findings suggest that mutant A\u03b2PP can cause mitochondrial dysfunction that is associated with long A\u03b2 but not with A\u03b242.<\/jats:p>","DOI":"10.3233\/jad-210366","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T12:59:25Z","timestamp":1628254765000},"page":"1039-1049","source":"Crossref","is-referenced-by-count":12,"title":["Mutations in the Amyloid-\u03b2 Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-\u03b2 Peptide"],"prefix":"10.1177","volume":"83","author":[{"given":"Chad A.","family":"Pope","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"University of Kansas Alzheimer\u2019s Disease Center, Kansas City, KS, USA"},{"name":"Department of 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