HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease

Abstract

2019) Neuropathology and Applied Neurobiology 45, 380-397 HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease Aims: Alzheimer's disease (AD) is characterized by degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the major cholinergic input to the cortical mantle and is related to cognitive decline in patients with AD. Cortical histone deacetylase (HDAC) dysregulation has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in CBF degeneration during AD onset is unknown. We investigated global HDAC protein levels and nuclear HDAC2 immunoreactivity in tissue containing the nbM, changes and their association with neurofibrillary tangles (NFTs) during the progression of AD. Methods: We used semi-quantitative western blotting and immunohistochemistry to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD) or severe AD (sAD). Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei and their colocalization with the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3 and Thioflavin-S, a marker of b-pleated sheet structures in NFTs. Results: In AD patients, HDAC2 protein levels were dysregulated in the basal forebrain region containing cholinergic neurons of the nbM. HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. Conclusions: These findings suggest that HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction, NFT pathology, and cognitive decline during clinical progression of AD.

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

“…Further analysis suggested that HDAC6 loss rendered neurons resistant to amyloid-b-mediated deterioration of mitochondrial trafficking, an prominent factor for AD (Govindarajan et al, 2013). The levels of HDAC2 were found to be altered in the basal forebrain region containing cholinergic neurons of the Nucleus Basalis of Meynert in AD patients (Mahady et al, 2018). Overexpression of HDAC3 in the hippocampus increased Ab levels, activated microglia, and decreased dendritic spine density in APPswe/PS1dE9 mice (Zhu et al, 2017).…”

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

“…Histone acetylation represents another layer of epigenomic regulation, and is hypothesized to play a role in LOAD pathogenesis (Graff et al, 2012). One study examined histone deacetylase activity in human brain tissue, specifically in cholinergic neurons containing pathological tau, and found that the abundance of histone deacetylase 2 (HDAC2) was reduced in females regardless of clinical diagnosis (normal, MCI or LOAD) (Mahady et al, 2019). As HDAC2 is involved in synaptic plasticity (Akhtar et al, 2009), neuroinflammation (Hsing et al, 2015) and cellular stress (Peng et al, 2015), gene dysregulation due to its reduction may be a contributing factor to neurodegeneration in the female brain.…”

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…Moreover, increased levels of HDAC2 and hypoacetylation have been found to negatively correlate with the mRNA expression level of genes associated with learning, memory and synaptic plasticity [341,352,376]. In addition, Graff et al [377] demonstrated that HDAG2 elevated levels epigenetically block the expression of neuroplasticity genes during neurodegeneration in the CK-p25 AD mouse model; whereas, in another AD mouse model, HDAC2 was found to be strongly expressed in the hippocampus and prefrontal cortex.…”