{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:52:04Z","timestamp":1792165924842,"version":"4.4.0"},"reference-count":65,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010473","name":"The Alzheimer\u2019s Foundation of America Award","doi-asserted-by":"publisher","award":["AWD00004772"],"award-info":[{"award-number":["AWD00004772"]}],"id":[{"id":"10.13039\/100010473","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Herb and Evelyn Abrams Family Amyloid Research Fund"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30AG066512"],"award-info":[{"award-number":["P30AG066512"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U24 NS141774"],"award-info":[{"award-number":["U24 NS141774"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U24NS135568"],"award-info":[{"award-number":["U24NS135568"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is a small-molecule oral drug that targets filamin A, a scaffolding protein in brain cells. Phase III clinical trials of simufilam failed to show any significant cognitive or functional improvements in AD patients. The purpose of this study is to identify and explain the molecular mechanisms that may have contributed to this drug\u2019s lack of clinical success. Methods: Our study investigates the effects of simufilam on amyloid processing, neuronal health, and mitochondrial functioning in the SH-SY5Y human neuronal cell model. SH-SY5Y cells were differentiated into neurons using 10 \u00b5M retinoic acid. Undifferentiated and differentiated SH-SY5Y were exposed to simufilam (5 \u00b5M, 50 \u00b5M; 24 hr). Results: Simufilam did not affect the expression of genes involved in amyloid processing. Amyloid precursor protein (APP), \u03b2-secretase, and \u03b1-secretase mRNA levels in simufilam-treated SH-SY5Y cells were all unchanged compared to untreated cells. However, amyloidogenic \u03b2-secretase protein was significantly increased (fold change 1.17) at 50 \u00b5M of simufilam only in differentiated SH-SY5Y cells without affecting APP or \u03b1-secretase protein expression. Simufilam at the 50 \u00b5M concentration reduced brain-derived neurotrophic factor protein levels (fold change 0.7) only in differentiated SH-SY5Y. Further, simufilam did not improve mitochondrial genes or structure. Conclusions: Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility.<\/jats:p>","DOI":"10.3390\/ph19020281","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Simufilam in Alzheimer\u2019s Disease: Assessment of Efficacy of a Controversial Drug in Human Neuronal Cell Culture"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7872-2183","authenticated-orcid":false,"given":"Ankita","family":"Srivastava","sequence":"first","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A.","family":"Renna","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahmina","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4568-4296","authenticated-orcid":false,"given":"Thomas","family":"Palaia","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1148-902X","authenticated-orcid":false,"given":"Aaron","family":"Pinkhasov","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving H.","family":"Gomolin","sequence":"additional","affiliation":[{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"De Leon","sequence":"additional","affiliation":[{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3379-8966","authenticated-orcid":false,"given":"Thomas","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Departments of Neurology, Pathology and Psychiatry, Center for Cognitive Neurology, Grossman School of Medicine, New York University, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-2441","authenticated-orcid":false,"given":"Allison B.","family":"Reiss","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"},{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"d\u2019Errico, P., and Meyer-Luehmann, M. 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