The double‐edged sword effect of HDAC6 in Aβ toxicities

Cheng, Kuan‐Chung; Hwang, Yu-Luen; Chiang, Hsueh‐Cheng

doi:10.1096/fj.202101061r

Cited by 2 publications

(2 citation statements)

References 51 publications

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“…[12] Moreover, HDAC6 engages in interactions with tau protein to promote tau hyperphosphorylation, which results in neurofibrillary tangles (NFTs) formation. [16,17] Therapeutics potential of HDAC6 inhibitors (HDAC6is) is gaining more interest after pharmacological treatments of some selective HDAC6is in AD models show reduction of tau levels, improvement in axonal transport and restoration of learning and memory, and anti-inflammatory activity. [4,[18][19][20] However the underlying role of HDAC6 in AD needs further investigation at cellular levels for the advancement of potential drug molecules.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology

Mondal,

Bai,

Gomm

et al. 2023

Advanced Science

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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.

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Section: Introductionmentioning

confidence: 99%

Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology

Mondal,

Bai,

Gomm

et al. 2023

Advanced Science

View full text Add to dashboard Cite

show abstract

“…Several studies have found increased HDAC6 in the brain of AD patients, leading to decreased levels of acetylated α -tubulin, destabilized microtubules of neurons, and eventually causing neuronal dysfunction 15 , 16 , 17 . In addition, HDAC6 elevates the tau protein phosphorylation and results in the A β -induced neuropathological change 18 , 19 . Accordingly, HDAC6 is emerging as a novel therapeutic target for AD treatment.…”

Section: Introductionmentioning

confidence: 99%