Cited by 134Alzheimer's disease research and treatmentsHistone Deacetylase Inhibitors ResearchDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 76 of the 76 references it cites were found in a registry or an index.

ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation

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Sen, Abhik, Nelson, Thomas J., Alkon, Daniel L.·2015·The Journal of Neuroscience

Abstract

Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

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Metadata

Authors
Sen, A., Nelson, T. J., & Alkon, D. L.
Affiliations
Blanchette Rockefeller Neurosciences Institute (US)
Venue
The Journal of Neuroscience
Published
2015-05-13
Volume
35
Issue
19
Pages
7538-7551
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1493503901
Cited by
133
References
76
Citations by year
2026: 10 · 2025: 11 · 2024: 10 · 2023: 7 · 2022: 12 · 2021: 17 · 2020: 11 · 2019: 10 · 2018: 17 · 2017: 11 · 2016: 13 · 2015: 4
FWCI
11.05
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, amyloid-beta oligomers, BDNF expression, histone deacetylase, histone H3 acetylation, LRP1, receptor-associated protein, protein kinase C epsilon, HDAC6, HDAC4, hippocampus, synaptic loss, Alzheimer's disease, epigenetic regulation, APOE3
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cell Nucleolus, Cells, Cultured, Cholesterol, Female, Gene Expression Regulation, Histone Deacetylases, Humans, Male, Mice, Transgenic, Middle Aged, Neuroblastoma, Neurons, Protein Kinase C, Case-Control Studies, Amyloid beta-Peptides, Brain-Derived Neurotrophic Factor, Protein Transport, Low Density Lipoprotein Receptor-Related Protein-1, RNA Interference, Cell Line, Tumor, Mice

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