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 deacet...
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Published in | Neuropathology and applied neurobiology Vol. 45; no. 4; pp. 380 - 397 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Wiley Subscription Services, Inc
01.06.2019
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS: LM conducted the research and composed the manuscript, MN assisted in data collection, MMA and KC provided statistical analysis, SEP edited the manuscript, and EJM assisted in research design and manuscript preparation. |
ISSN: | 0305-1846 1365-2990 |
DOI: | 10.1111/nan.12518 |