{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T09:34:56Z","timestamp":1793525696935,"version":"4.5.0"},"reference-count":71,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T00:00:00Z","timestamp":1656201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Aging (NIA\/NIH)","award":["NIH R01 (1R01AG062254)"],"award-info":[{"award-number":["NIH R01 (1R01AG062254)"]}]},{"name":"National Institute on Aging (NIA\/NIH)","award":["2P01AG012411-17A1"],"award-info":[{"award-number":["2P01AG012411-17A1"]}]},{"name":"National Institute on Aging (NIA\/NIH)","award":["I01 BX001655"],"award-info":[{"award-number":["I01 BX001655"]}]},{"name":"National Institute on Aging (NIA\/NIH)","award":["IK6 BX004851"],"award-info":[{"award-number":["IK6 BX004851"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["NIH R01 (1R01AG062254)"],"award-info":[{"award-number":["NIH R01 (1R01AG062254)"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["2P01AG012411-17A1"],"award-info":[{"award-number":["2P01AG012411-17A1"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["I01 BX001655"],"award-info":[{"award-number":["I01 BX001655"]}]},{"name":"U.S. Dept. of Veteran Affairs","award":["IK6 BX004851"],"award-info":[{"award-number":["IK6 BX004851"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer\u2019s disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [\u03b54, \u03b54] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington\u2019s disease) and of Alzheimer\u2019s-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD.<\/jats:p>","DOI":"10.3390\/pharmaceutics14071354","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T21:01:41Z","timestamp":1656277301000},"page":"1354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Akshatha","family":"Ganne","sequence":"first","affiliation":[{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"},{"name":"Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshisundaram","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Sue T.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"},{"name":"BioInformatics Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-0734","authenticated-orcid":false,"given":"Robert J.","family":"Shmookler Reis","sequence":"additional","affiliation":[{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"},{"name":"Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"BioInformatics Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Ayyadevara","sequence":"additional","affiliation":[{"name":"Central Arkansas Veterans Healthcare Service, Little Rock, AR 72205, USA"},{"name":"Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"BioInformatics Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a021642","DOI":"10.1101\/cshperspect.a021642","article-title":"Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin","volume":"9","author":"Hol","year":"2017","journal-title":"Cold Spring Harb. 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