{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:13:35Z","timestamp":1790324015078,"version":"4.1.0"},"reference-count":81,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Deposition of amyloid \u03b2\u2010protein (A\u03b2) is a hallmark of Alzheimer's disease (AD), produced by \u03b3\u2010secretase\u2013mediated cleavage of amyloid precursor protein (APP). The 90\u2010kDa heat shock protein (Hsp90) co\u2010chaperone, activator of Hsp90 ATPase homolog 1 (AHA1), is known to promote the accumulation of toxic tau species; however, its effects on A\u03b2 production remain unclear. Using cellular models\u2014including human embryonic kidney 293\u2009T (HEK293T) cells, stable HEK\u2010APP cells, presenilin 1\/2 double\u2010knockout mouse embryonic fibroblasts (PS\u2010DKO MEFs), and Chinese hamster ovary (CHO) cells\u2014in which AHA1 was experimentally manipulated, together with observational analyses of human iPSC\u2010derived neurons carrying an FAD\u2010linked APP mutation, we demonstrate that AHA1 regulates A\u03b2 generation through two mechanisms: regulation of APP protein abundance through pathways that are at least partially independent of Hsp90 interaction and Hsp90\u2010dependent promotion of \u03b3\u2010secretase assembly. Knockdown of endogenous AHA1 reduces A\u03b2 production and decreases APP and \u03b3\u2010secretase component levels, whereas AHA1 overexpression elevates A\u03b2 generation and increases the expression of these proteins. The AHA1\u2010E67K mutant, which has impaired Hsp90 binding, lowers A\u03b2 production and the levels of APP and \u03b3\u2010secretase components compared with wild\u2010type AHA1. AHA1 associates with APP and APH1, an immature \u03b3\u2010secretase component, indicating its role in APP proteolysis and A\u03b2 production. Disruption of the AHA1\/Hsp90 complex\u2014through AHA1 knockdown, the E67K mutant, or a small\u2010molecule inhibitor\u2014reduces \u03b3\u2010secretase assembly. Notably, Familial AD mutations (APP\u2010C99\u2010I45F, PS1\u2010L286V) upregulate AHA1\/Hsp90, elevating APP\/APH1 and A\u03b242 production. AHA1 knockdown rescues FAD\u2010linked A\u03b242 overproduction in a mutant cell model, while AHA1 overexpression exacerbates PS1 mutant A\u03b2 production. Collectively, these findings reveal that AHA1 regulates A\u03b2 production by modulating APP abundance and \u03b3\u2010secretase assembly, establishing AHA1 as a potential target for therapeutic intervention in AD.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70544-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70544","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:46:06Z","timestamp":1787895966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>AHA1<\/scp>\n                    Regulates A\u03b2 Production via Modulation of\n                    <scp>APP<\/scp>\n                    Abundance and \u03b3\u2010Secretase Assembly"],"prefix":"10.1111","volume":"170","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9946-3746","authenticated-orcid":false,"given":"Arshad Ali","family":"Noorani","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry The University of Kansas  Lawrence Kansas USA"},{"name":"Department of Pharmacology &amp; Immunology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadequl","family":"Islam","sequence":"additional","affiliation":[{"name":"Department of Neuro\u2010Oncology, Institute of Brain Science, Graduate School of Medical Sciences Nagoya City University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-3050","authenticated-orcid":false,"given":"Emma","family":"Filip","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Notre Dame  Notre Dame Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1916-2682","authenticated-orcid":false,"given":"Kevin","family":"Catalfano","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Notre Dame  Notre Dame Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-6257","authenticated-orcid":false,"given":"Shravan","family":"Paswan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Immunology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"School of Natural Sciences (Biology) Northwest Missouri State University  Maryville Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-4544","authenticated-orcid":false,"given":"Heather M.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"University of Kansas Alzheimer's Disease Research Center University of Kansas Medical Center  Kansas Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6200-3480","authenticated-orcid":false,"given":"Brian S. 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