Direct Transcriptional Effects of Apolipoprotein E
Open accessAbstract
A major unanswered question in biology and medicine is the mechanism by which the product of the apolipoprotein E ε4 allele, the lipid-binding protein apolipoprotein E4 (ApoE4), plays a pivotal role in processes as disparate as Alzheimer's disease (AD; in which it is the single most important genetic risk factor), atherosclerotic cardiovascular disease, Lewy body dementia, hominid evolution, and inflammation. Using a combination of neural cell lines, skin fibroblasts from AD patients, and ApoE targeted replacement mouse brains, we show in the present report that ApoE4 undergoes nuclear translocation, binds double-stranded DNA with high affinity (low nanomolar), and functions as a transcription factor. Using chromatin immunoprecipitation and high-throughput DNA sequencing, our results indicate that the ApoE4 DNA binding sites include ∼1700 gene promoter regions. The genes associated with these promoters provide new insight into the mechanism by which AD risk is conferred by ApoE4, because they include genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis. SIGNIFICANCE STATEMENT This study shows for the first time that apolipoprotein E4 binds DNA with high affinity and that its binding sites include 1700 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 Alzheimer's disease pathogenesis.
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APOE directly binds to promoter regions of SIRT1 to promote transcription in neurons.
“Apart from direct biochemical support to sustain myelin synthesis, it was demonstrated that APOE directly binds to promoter regions of SIRT1 to promote transcription in neurons (Theendakara et al. 2016).”
From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Theendakara et al. 2016
The Discussion reports that ApoE binds the SirT1 promoter, but says it represses promoter activity rather than promoting transcription. In the ‘ApoE binds to the SirT1 promoter’ section, SirT1 promoter-reporter activity fell in human neuroblastoma cells expressing ApoE3 or ApoE4. (LLM, conf=0.92)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAlterations in gene expression associated with ApoE4 potentiate apoptotic and inflammatory pathways.
“the referred alterations in gene expression associated to ApoE4 potentiate apoptotic and inflammatory pathways [37,43]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [37]
The Discussion (page not provided) reports ApoE4-associated repression of MADD, ADNP, and COMMD6, and the results report increased inflammatory cytokine expression. But the Discussion says these changes “could participate” in triggering inflammatory and apoptotic pathways; it does not establish that both pathways are potentiated as the claim states. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoE4 directly interacts with promoter region of MADD, ADNP, COMMD6 and PPP2R5E genes, decreasing their expression.
“ApoE4 also directly interacts with the promoter region of MAPK activating death domain (MADD), activity dependent neuroprotector homeobox (ADNP), COMM domain containing 6 (COMMD6) and protein phosphatase 2, regulatory subunit B’, epsilon isoform (PPP2R5E) genes, decreasing their expression.”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [37]
The Discussion says ChIP-seq found ApoE4 interactions with the MADD, ADNP, and COMMD6 promoters and reports reduced transcription of those genes. Table 3 lists PPP2R5E among genes associated with ApoE4 binding, but the paper does not report decreased PPP2R5E expression. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBy affecting NRF1 transcriptional role, ApoE4 influences expression of its target genes, potentially involved in mitochondrial dynamics and Ca2+ handling.
“By affecting NRF1 transcriptional role, ApoE4 then influences the expression of its target genes, potentially involved in mitochondrial dynamics and Ca2+ handling [37].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [37]
The Discussion reports that ApoE4 binds gene promoters and reduces transcription of SirT1, MADD, ADNP, and COMMD6. But our copy does not identify NRF1 as the mediator or establish that changes to NRF1 target genes affect mitochondrial dynamics or Ca2+ handling (searched: NRF1, mitochondrial dynamics, calcium handling). (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoE can translocate to the nucleus, bind DNA, and function as a transcription factor in human glioblastoma cells.
“Recently, it was shown that ApoE can translocate to nucleus, bind DNA, and function as a transcription factor in human glioblastoma cells [53].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [53]
ApoE4 binds the promoter regions of ∼1700 genes, including genes associated with synaptic function, neuroinflammation, and insulin resistance.
“Genome-wide mapping of ApoE binding site indicated that ApoE4 binds the promoter regions of ∼1700 genes, including genes associated with synaptic function, neuroinflammation, and insulin resistance.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [53]
APOE4 acquires a novel function in the nucleus, where it translocates and directly binds DNA to affect transcription of genes associated with AD.
“In addition to the classical role of APOE in cholesterol transport, APOE4 acquires a novel function in the nucleus, where it translocates and directly binds DNA to affect the transcription of genes associated with AD 45,46 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [46]
ApoE4 may act as a transcription factor, regulating the expression of genes potentially involved in cellular and molecular pathways related to Alzheimer's disease development.
“recent studies postulate that ApoE4 may act as a transcription factor, regulating the expression of genes potentially involved in cellular and molecular pathways related to AD development [37].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [37]
ApoE4 directly binds to promoter region of SIRT1 gene, decreasing its expression and enzymatic activity.
“ApoE4 was reported to directly bind to the promoter region of SIRT1 gene, [37], decreasing its expression and enzymatic activity.”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [37]
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- Authors
- Theendakara, V., Peters-Libeu, C. A., Spilman, P., Poksay, K. S., Bredesen, D. E., & Rao, R. V.
- Affiliations
- Buck Institute for Research on Aging (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-01-20
- Volume
- 36
- Issue
- 3
- Pages
- 685-700
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4719010
- OpenAlex
- W2318325474
- Cited by
- 152
- References
- 55
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 14 · 2023: 13 · 2022: 13 · 2021: 22 · 2020: 11 · 2019: 21 · 2018: 16 · 2017: 17 · 2016: 12
- FWCI
- 17.72
- 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)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Marin Community Foundation
- National Institutes of Health
- National Institute on Aging (AG034427, R01AG034427)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, transcription factors, DNA binding, promoter binding sites, nuclear translocation, Alzheimer's disease risk, gene expression regulation, neurotrophins, programmed cell death, synaptic function, sirtuins, aging, insulin resistance, microtubule disassembly
- MeSH terms
- Aged, Animals, Base Sequence, Brain, Female, Fibroblasts, Humans, Male, Mice, Transgenic, Middle Aged, Molecular Sequence Data, Neurons, Protein Binding, Transcription, Genetic, Mice, Knockout, Cell Line, Tumor, Mice, Apolipoprotein E4
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