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Martinos Center for Biomedical Imaging, Massachusetts General Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018500","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity \u2010 with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D\u2010AD\u00a0human neural culture model. Results suggest that the structure\u2010based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear A\u03b2 deposits by upregulating phagocytosis, improve tubulin\/microtubule network by enhancing acetyl \u03b1\u2010tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho\u2010tau (p\u2010tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology\u2010based drug discovery in AD.<\/jats:p>","DOI":"10.1002\/advs.202304545","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T18:49:18Z","timestamp":1700765358000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Structure\u2010Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-449X","authenticated-orcid":false,"given":"Prasenjit","family":"Mondal","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital Harvard Medical School Boston  Charlestown Boston MA 02114 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4587-8426","authenticated-orcid":false,"given":"Ping","family":"Bai","sequence":"additional","affiliation":[{"name":"Athinoula A. 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