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Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer’s disease model mice
Fukui M, Kaise T, Masaki T, Sakamoto T, Kageyama R.. Cell reports, 2025-12-26
Topic: Disease mechanisms in lab and animal studies
Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously demonstrated that a treatment of inducing Plagl2 , a zinc finger transcription factor gene, and antagonizing Dyrk1a , a gene associated with Down syndrome, referred to as iPaD, can functionally rejuvenate aged neural stem cells (NSCs), thereby enhancing neurogenesis and improving cognition in aged mice. Here, we found that NSC-specific iPaD treatment effectively activated neurogenesis, reduced amyloid-β deposition, and improved cognitive function in Alzheimer’s disease model mice. Transcriptomic analysis revealed widespread significant changes in gene expression in the hippocampus following iPaD treatment. The upregulated genes included those associated with the activation of astrocytes and microglia involved in amyloid-β clearance, while the downregulated genes included several that are upregulated in Alzheimer’s disease patients, but whose roles in disease progression remain unclear. Among the latter genes, knockdown of Prkag2 , a gene encoding protein kinase AMP-activated non-catalytic subunit gamma 2, in the hippocampus most effectively enhanced neurogenesis and reduced amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activated AMP-activated protein kinase signaling, thereby upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer’s disease.
Key findings
- We previously demonstrated that a treatment of inducing Plagl2 , a zinc finger transcription factor gene, and antagonizing Dyrk1a , a gene associated with Down syndrome, referred to as iPaD, can functionally rejuvenate aged neural stem cells (NSCs), thereby enhancing neurogenesis and improving cognition in aged mice.
- Here, we found that NSC-specific iPaD treatment effectively activated neurogenesis, reduced amyloid-β deposition, and improved cognitive function in Alzheimer’s disease model mice.
- Transcriptomic analysis revealed widespread significant changes in gene expression in the hippocampus following iPaD treatment.
- The upregulated genes included those associated with the activation of astrocytes and microglia involved in amyloid-β clearance, while the downregulated genes included several that are upregulated in Alzheimer’s disease patients, but whose roles in disease progression remain unclear.
- These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer’s disease.
Study details
- Evidence strengthLow
How this study scored 40/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cell reports) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Fukui, M., Kaise, T., Masaki, T., Sakamoto, T., & Kageyama, R. (2025). Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer’s disease model mice. Cell reports. https://doi.org/10.64898/2025.12.24.696442
Vancouver
Fukui M, Kaise T, Masaki T, Sakamoto T, Kageyama R. Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer’s disease model mice. Cell reports. 2025. doi:10.64898/2025.12.24.696442.
BibTeX
@article{fukui2025-53d5ab2a,
author = {Fukui, M. and Kaise, T. and Masaki, T. and Sakamoto, T. and Kageyama, R.},
title = {{Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer’s disease model mice}},
journal = {Cell reports},
year = {2025},
doi = {10.64898/2025.12.24.696442},
url = {https://doi.org/10.64898/2025.12.24.696442}
}
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