Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology
Abstract 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 pri...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202304545 |
| _version_ | 1797365325460668416 |
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| author | Prasenjit Mondal Ping Bai Ashley Gomm Grisilda Bakiasi Chih‐Chung Jerry Lin Yanli Wang Se Hoon Choi Rudolph E. Tanzi Changning Wang Can Zhang |
| author_facet | Prasenjit Mondal Ping Bai Ashley Gomm Grisilda Bakiasi Chih‐Chung Jerry Lin Yanli Wang Se Hoon Choi Rudolph E. Tanzi Changning Wang Can Zhang |
| author_sort | Prasenjit Mondal |
| collection | DOAJ |
| description | Abstract 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 ‐ 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‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) 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‐based drug discovery in AD. |
| first_indexed | 2024-03-08T16:48:28Z |
| format | Article |
| id | doaj.art-dc1603e8e7de47d08dce3a1227f667ad |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T16:48:28Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-dc1603e8e7de47d08dce3a1227f667ad2024-01-05T08:26:58ZengWileyAdvanced Science2198-38442024-01-01111n/an/a10.1002/advs.202304545Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease NeuropathologyPrasenjit Mondal0Ping Bai1Ashley Gomm2Grisilda Bakiasi3Chih‐Chung Jerry Lin4Yanli Wang5Se Hoon Choi6Rudolph E. Tanzi7Changning Wang8Can Zhang9Genetics 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 USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital Harvard Medical School Building 149, Charlestown Boston MA 02129 USAGenetics 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 USAGenetics 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 USAGenetics 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 USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital Harvard Medical School Building 149, Charlestown Boston MA 02129 USAGenetics 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 USAGenetics 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 USAAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital Harvard Medical School Building 149, Charlestown Boston MA 02129 USAGenetics 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 USAAbstract 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 ‐ 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‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) 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‐based drug discovery in AD.https://doi.org/10.1002/advs.202304545acetylationAlzheimer's diseaseepigeneticHDAC6 inhibitorneuroinflammationphagocytosis |
| spellingShingle | Prasenjit Mondal Ping Bai Ashley Gomm Grisilda Bakiasi Chih‐Chung Jerry Lin Yanli Wang Se Hoon Choi Rudolph E. Tanzi Changning Wang Can Zhang Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology Advanced Science acetylation Alzheimer's disease epigenetic HDAC6 inhibitor neuroinflammation phagocytosis |
| title | Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology |
| title_full | Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology |
| title_fullStr | Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology |
| title_full_unstemmed | Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology |
| title_short | Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology |
| title_sort | structure based discovery of a small molecule inhibitor of histone deacetylase 6 hdac6 that significantly reduces alzheimer s disease neuropathology |
| topic | acetylation Alzheimer's disease epigenetic HDAC6 inhibitor neuroinflammation phagocytosis |
| url | https://doi.org/10.1002/advs.202304545 |
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