ApoE4 attenuates autophagy via FoxO3a repression in the brain
Open accessAbstract
Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.
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Intraneuronal Aβ correlates with the apolipoprotein E4 (ApoE4) genotype, which has been described to downregulate autophagy.
“Another piece of evidence for the role of autophagy in intraneuronal Aβ accumulation is the finding that intraneuronal Aβ correlates with the apolipoprotein E4 (ApoE4) genotype [21], the main known genetic risk factor for AD, which has been described to downregulate autophagy [108].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [108]
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References 70 · Cited by 54
- Authors
- Sohn, H.-Y., Kim, S.-I., Park, J.-Y., Park, S.-H., Koh, Y. H., Kim, J., & Jo, C.
- Affiliations
- Korea University (KR)
- Seoul National University (KR)
- Korea National Institute of Health (KR)
- Corresponding author
- Kim, Joon
- Jo, Chulman
- Venue
- Scientific Reports
- Published
- 2021-09-02
- Volume
- 11
- Issue
- 1
- Pages
- 17604-17604
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8413297
- OpenAlex
- W3198119075
- Cited by
- 54
- References
- 70
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 10 · 2023: 10 · 2022: 9 · 2021: 1
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Research of Korea Disease Control and Prevention Agency
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- APOE ε4, apolipoprotein E, FOXO3, autophagy, mitophagy, Alzheimer's disease, APOE ε4 carriers, FOXO3a phosphorylation, Beclin-1, ATG12, BNIP3, PINK1, tau phosphorylation, brain
- MeSH terms
- Forkhead Box Protein O3, Alzheimer Disease, Autophagy, Brain, Humans, Phosphorylation, Apolipoprotein E4, Mitophagy
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