ApoE4 Upregulates GSK ‐3β to Aggravate Alzheimer‐Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice
Yuying Wang, Yang Gao, Yarong Wang, Fuqiang Zhang, Fei Sun, Xin Wang, Jiazhao Xie, Zhipeng Xu et al.. CNS Neuroscience & Therapeutics, 2025-09-01
Topic: Brain proteins, microglia and lab models
We observed that GSK-3β activity was significantly upregulated in ApoE4 mice, accompanied by disruption of the insulin signaling pathway. Notably, ApoE4-T2DM mice exhibited exacerbated AD-related pathologies, including increased accumulation of hyperphosphorylated tau, neuroinflammation, and synaptic loss. These changes were correlated with more severe cognitive impairments compared with ApoE3-T2DM or ApoE4 mice. Furthermore, inhibition of GSK-3β activity using the selective inhibitor 9-ING-41 effectively ameliorated both AD-like pathologies and cognitive deficits in ApoE4-T2DM mice. Our findings suggest that ApoE4 exacerbates AD pathogenesis by activating GSK-3β. Furthermore, targeting GSK-3β may offer a promising therapeutic strategy to halt the progression from T2DM to AD, providing new insights into potential interventions for patients at risk.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Wang, Y., Gao, Y., Wang, Y., Zhang, F., Sun, F., Wang, X., et al. (2025). ApoE4 Upregulates GSK ‐3β to Aggravate Alzheimer‐Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice. CNS Neuroscience & Therapeutics. https://doi.org/10.1111/cns.70575
Vancouver
Wang Y, Gao Y, Wang Y, Zhang F, Sun F, Wang X, et al. ApoE4 Upregulates GSK ‐3β to Aggravate Alzheimer‐Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice. CNS Neuroscience & Therapeutics. 2025. doi:10.1111/cns.70575. PMID: 40905109.
BibTeX
@article{wang2025-40905109,
author = {Wang, Yuying and Gao, Yang and Wang, Yarong and Zhang, Fuqiang and Sun, Fei and Wang, Xin and Xie, Jiazhao and Xu, Zhipeng and others},
title = {{ApoE4 Upregulates GSK ‐3β to Aggravate Alzheimer‐Like Pathologies and Cognitive Impairment in Type 2 Diabetic Mice}},
journal = {CNS Neuroscience \& Therapeutics},
year = {2025},
doi = {10.1111/cns.70575},
pmid = {40905109},
url = {https://doi.org/10.1111/cns.70575}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We observed that GSK-3β activity was significantly upregulated in ApoE4 mice, accompanied by disruption of the insulin signaling pathway.
- Notably, ApoE4-T2DM mice exhibited exacerbated AD-related pathologies, including increased accumulation of hyperphosphorylated tau, neuroinflammation, and synaptic loss.
- These changes were correlated with more severe cognitive impairments compared with ApoE3-T2DM or ApoE4 mice.
- Furthermore, inhibition of GSK-3β activity using the selective inhibitor 9-ING-41 effectively ameliorated both AD-like pathologies and cognitive deficits in ApoE4-T2DM mice.
- Our findings suggest that ApoE4 exacerbates AD pathogenesis by activating GSK-3β.
Why it matters
In mice with type 2 diabetes, ApoE4 worsened Alzheimer-like pathologies and cognitive impairment, and inhibiting GSK-3β with 9-ING-41 improved both in these mice. These are animal findings, and the authors suggest targeting GSK-3β may be a promising strategy, which still requires testing in humans.
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Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (CNS Neuroscience & Therapeutics) |
| Journal's citation record | 1 / 4 | CNS Neuroscience & Therapeutics: journal h-index 120 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Jian–Zhi Wang: h-index 21 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Huazhong University of Science and Technology: institution h-index 934 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40905109) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1111/cns.70575
- PubMed: 40905109
- Original source →
- Free full text: CNS Neuroscience & Therapeutics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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