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O2‐02‐03: HDAC1 Sumoylation Protects Against Amyloid‐Beta Toxicity in a Mouse Model of Alzheimer's Disease
Author(s) -
Lee Eminy,
Tao Chijay,
Hsu Wei-Lun,
Ma Yun-Li
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.401
Subject(s) - sumo protein , histone , hdac1 , acetylation , microbiology and biotechnology , hippocampus , neuroprotection , amyloid beta , senile plaques , chemistry , histone deacetylase , biology , alzheimer's disease , pharmacology , neuroscience , ubiquitin , biochemistry , medicine , disease , gene , peptide
Background: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder for which there are no effective treatments. By far the strongest genetic risk factor for AD is possession of the e4 allele of apolipoprotein E (ApoE4), a protein involved in lipid transport. Despite knowing for over a decade that the ApoE e4 allele is somehow contributory to the disease process, the precise role of ApoE4 in the AD pathogenesis remains unclear. We now provide evidence that ApoE4 acts as a transcription factor, binds DNA with high affinity, including the promoter regions of 1700 different genes, several of which have previously been linked to AD pathogenesis. Methods: Through a series of experiment involving neural cells, fibroblasts from AD patients, and hApoEKI-Tg brains and using a combination of techniques including ChiP-Seq, SPR, and IHC, we show that ApoE4 undergoes nuclear translocation, binds double-stranded DNA with high affinity and functions as a transcription factor. Results: Our results indicate that ApoE not only binds to the SirT1 promoter with high affinity but also represses SirT1 promoter activity, suggesting a plausible role for ApoE4 in the nucleus as a transcriptional repressor. ChIP sequencing data indicate that the ApoE4 DNA binding sites include w1700 gene promoter regions that include genes associated with neurotrophins, programmed cell death, synaptic function, sirtuins and aging, and insulin resistance, all processes that have been implicated in AD pathogenesis. Further experiments revealed that ApoE4 reduced transcription of at least two genes besides SirT1 and both of these genes are involved in inflammatory processes. Thus, ApoE4 leads to an entire reprogramming of the cell, with increased inflammatory response and increased AD-related signaling. Conclusions: ApoE4 functions as a transcription factor, binding DNA and modulating the transcription of >3000 genes and approximately half of these did not bind ApoE3. Notably, ApoE4 targets genes associated with sirtuins and aging, neurotrophins and programmed cell death, microtubule disassembly, synaptic function, NFkB and inflammation, and insulin resistance and diabetes, providing a roadmap for what is essentially a ‘unified theory’ of Alzheimer’s disease.