Histone Acetylation Modifiers in the Pathogenesis of Alzheimerâ€™s Disease

Lu, Xi; Wang, Li; Yu, Caijia; Yu, Daohai; Yu, Gang

doi:10.3389/fncel.2015.00226

Cited by 92 publications

(78 citation statements)

References 83 publications

(127 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Histone H4, on the other hand, revealed a 6.9‐fold increase in synthesis in K3 mice, representing the largest fold‐change in our proteomic analysis. Histone H4 plays a crucial role in regulating chromatin formation, with its total levels and extent of acetylation suggested to be altered in AD (Lu et al , ; Narayan et al , ).…”

Section: Discussionmentioning

confidence: 99%

Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

et al. 2019

View full text Add to dashboard Cite

Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid‐β, the second hallmark of AD, induces de novo protein synthesis of tau. Importantly, this activation was found to be tau‐dependent, raising the question of whether FTD‐tau by itself affects protein synthesis. We therefore applied non‐canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identified changes in 247 proteins of the de novo proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Therefore, the study of increasing histone acetylation to ameliorate the impairment of memory in AD patients may be a promising strategy. Generally, histone acetylation usually activates gene transcription, whereas histone deacetylation is closely associated with gene transcriptional repression [15]. Both of them alter chromatin structure and transcription factors for the regulation of gene expression.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease

Yang

Zhang

Wang

et al. 2017

Transl Neurodegener

125

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Although HDAC inhibitors have the ability to ameliorate cognitive impairment, successful treatments in the classic AD animal model are rarely translated into clinical trials. As for the reduction of unwanted side effects, the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed. The review focused on literatures on epigenetic mechanisms in recent years, especially on histone acetylation in terms of the enhancement of specificity, efficacy and avoiding side effects for treating AD.

show abstract

“…HDAC-mediated deacetylation of histone proteins promotes chromatin condensation and gene repression. HDAC inhibition mitigates a broad range of experimental neuropathological phenotypes associated with neurodegenerative diseases, traumatic brain injury, and ischemic stroke (8,24,30). However, the precise mechanism by which HDAC inhibition mediates neuroprotection is not well delineated.…”

Section: Introductionmentioning

confidence: 99%

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

Wang

Kinoshita

et al. 2018

Brain Pathology

View full text Add to dashboard Cite

Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.

show abstract

Histone Acetylation Modifiers in the Pathogenesis of Alzheimerâ€™s Disease

Cited by 92 publications

References 83 publications

Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

Decreased synthesis of ribosomal proteins in tauopathy revealed by non‐canonical amino acid labelling

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

Contact Info

Product

Resources

About