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HDAC 2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease
Author(s) -
Mahady L.,
Nadeem M.,
MalekAhmadi M.,
Chen K.,
Perez S. E.,
Mufson E. J.
Publication year - 2019
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12518
Subject(s) - nucleus basalis , basal forebrain , cholinergic neuron , cholinergic , cognitive decline , neuroscience , pathology , choline acetyltransferase , alzheimer's disease , biology , histone deacetylase , medicine , dementia , histone , disease , biochemistry , gene
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 HDAC 2 protein levels in individual cholinergic nbM nuclei and their colocalization with the early phosphorylated tau marker AT 8, the late‐stage apoptotic tau marker TauC3 and Thioflavin‐S, a marker of β‐pleated sheet structures in NFT s. Results In AD patients, HDAC 2 protein levels were dysregulated in the basal forebrain region containing cholinergic neurons of the nbM. HDAC 2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages. HDAC 2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. Conclusions These findings suggest that HDAC 2 dysregulation contributes to cholinergic nbM neuronal dysfunction, NFT pathology, and cognitive decline during clinical progression of AD .