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
Open accessAbstract
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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“In another study, ApoE4 increased the nuclear translocation of histone deacetylases (HDACs) in human neuroblastomas, thereby reducing brain derived neurotrophic factor expression [54].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [54]
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“In contrast, ApoE3 retains HDACs in the cytosol via elevating the expression of protein kinase C ε.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [54]
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“Of note, sApoE has been found to influence the transcriptome by modulating histone acetylation (68, 69).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [69]
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“In the brains of Alzheimer's disease patients, nuclear translocation of HDA6 was increased as compared with controls.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [54]
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Cites
1 retracted
Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease
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RetractedAnalyzing real-time PCR data by the comparative CT method
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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
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Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism
Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J., & Greenberg, M. E. (1998) · Neuron · doi:10.1016/s0896-6273(00)81010-7 · Cited by 1,561
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Yang, X., & Seto, E. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2346 · Cited by 1,277
Recovery of learning and memory is associated with chromatin remodelling
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Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
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Regulation of histone acetylation during memory formation in the hippocampus
Levenson, J. M., O'Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., & Sweatt, J. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402229200 · Cited by 1,131
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Sorted by citations
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870
Brain-Derived Neurotrophic Factor in Alzheimer’s Disease and Its Pharmaceutical Potential
Gao, L., Zhang, Y., Sterling, K., & Song, W. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00279-0 · Cited by 606
Numakawa, T., Odaka, H., & Adachi, N. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113650 · Cited by 367
Shinohara, M., Tachibana, M., Kanekiyo, T., & Bu, G. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075796 · Cited by 297
Shen, S., & Kozikowski, A. P. (2016) · ChemMedChem · doi:10.1002/cmdc.201500486 · Cited by 288
Metadata
- Authors
- Sen, A., Nelson, T. J., & Alkon, D. L.
- Affiliations
- Blanchette Rockefeller Neurosciences Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-05-13
- Volume
- 35
- Issue
- 19
- Pages
- 7538-7551
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6705431
- 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
- hybrid
- doi.org
- Licence
- 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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