APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice
Open accessAbstract
APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), particularly associated with increased levels of amyloid-β (Aβ) and amyloid deposition. However, it remains unclear whether APOE4 is associated with greater tau phosphorylation and neurofibrillary tangle formation, a hallmark of AD leading to structural disruption of the neuronal cytoskeleton. The current study used 3 and 7 month old EFAD mice, which express human APOE and over-express specifically human Aβ42 via 5 familial-AD (FAD) mutations, to investigate APOE genotype-specific effects on site-specific tau phosphorylation. The results reveal that AD-like site-specific tau phosphorylation was increased in E4FAD mice, accompanied by disrupted cortical neuronal morphology, compared to E3FAD mice. Further analysis demonstrated that the levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3β, were significantly increased in E4FAD mice compared to E3FAD mice. These results suggest that the APOE4 genotype contributes to increased site-specific tau phosphorylation via activation of the calpain-CDK5 signaling pathway.
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APOE4 and hyperactive GSK-3β further promote both mitochondrial dysfunction and proteotoxic accumulation.
“Consistent with this view, the presence of APOE4 and hyperactive GSK-3β, well-established AD risk factors, further promotes both mitochondrial dysfunction and proteotoxic accumulation [65], illustrating the integrated nature of these hypotheses.”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [65]
Specific overexpression of human ApoE4 in neurons, but not astrocytes, increases tau phosphorylation in mouse brains compared to ApoE3 overexpression.
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From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [129]
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- Authors
- Zhou, M., Huang, T., Collins, N., Zhang, J., Shen, H., Dai, X., Xiao, N., Wu, X., Wei, Z., York, J., Lin, L., Zhu, Y., Jo LaDu, M., & Chen, X.
- Affiliations
- Fujian Medical University (CN)
- ORCID
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2016-07-20
- Volume
- 13
- Issue
- 9
- Pages
- 1048-1055
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2342360760
- Cited by
- 40
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 2
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- cc-by
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, tau phosphorylation, calpain, cyclin-dependent kinase 5, familial Alzheimer's disease, amyloid-beta 42, neurofibrillary tangles, p35, p25, GSK3β
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Aging, Animals, Calpain, Cerebral Cortex, Humans, Male, Mice, Transgenic, Mutation, Neurons, Peptide Fragments, Phosphorylation, Signal Transduction, Amyloid beta-Peptides, tau Proteins, Cyclin-Dependent Kinase 5, Apolipoprotein E4
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