Abstract:
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 β-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.
journal_name
Neuropathol Appl Neurobioljournal_title
Neuropathology and applied neurobiologyauthors
Mahady L,Nadeem M,Malek-Ahmadi M,Chen K,Perez SE,Mufson EJdoi
10.1111/nan.12518subject
Has Abstractpub_date
2019-06-01 00:00:00pages
380-397issue
4eissn
0305-1846issn
1365-2990journal_volume
45pub_type
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