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ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease
Tang X, Walter E, Wohleb E, Fan Y, Wang C.. Autophagy, 2023-11-10
Topic: Brain proteins, microglia and lab models
Macroautophagy/autophagy is the intracellular degradation process of cytoplasmic content and damaged organelles. Autophagy is strongly associated with the progression of Alzheimer disease (AD). Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration. Postnatal neurogenesis, the generation of new neurons from adult neural stem cells (NSCs), is impaired in AD patients as well as in AD animal models. However, the extent to which microglial autophagy influences adult NSCs and neurogenesis in AD animal models has not been studied. Here, we showed that conditional knock out (cKO) of Atg5 (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model. Interestingly, the protection of neurogenesis by Atg5 in microglia was only observed in female AD mice. To confirm the roles of autophagy in microglia for postnatal hippocampal neurogenesis, we generated additional cKO mice to delete autophagy essential genes Rb1cc1 or Atg14 in microglia. However, these rb1cc1 cKO and atg14 cKO mice did not exhibit neurogenesis defects in the context of a female AD mouse model. Last, we used the CSF1R antagonist to deplete ATG5-deficient microglia and this intervention restored neurogenesis in the hippocampus of 5×FAD mice. These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD. Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration. Abbreviations: 5×FAD: familial Alzheimer disease; Aβ: β-amyloid; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; ATG: autophagy related; BrdU: 5-bromo-2'-deoxyuridine; CA: Cornu Ammonis; cKO: conditional knock out; CSF1R: colony stimulating factor 1 receptor; Ctrl: control; DCX: doublecortin; DG: dentate gyrus; GFAP: glial fibrillary acidic protein; GZ: granular zone; H&E: hematoxylin and eosin; IF: immunofluorescence; LD: lipid droplet; LDAM: lipid droplets accumulated microglia; LPS: lipopolysaccharides; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; NSCs: neural stem cells; RB1CC1: RB1-inducible coiled-coil 1; SOX2: SRY (sex determining region Y)-box 2; SGZ: subgranular zone; SVZ: subventricular zone; WT: wild type.
Key findings
- Autophagy is strongly associated with the progression of Alzheimer disease (AD).
- Microglia are brain-resident macrophages, and recent studies indicate that autophagy in microglia protects neurons from neurodegeneration.
- Here, we showed that conditional knock out (cKO) of Atg5 (autophagy related 5) in microglia inhibited postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus, but not in the subventricular zone (SVZ) of a 5×FAD mouse model.
- These results indicate that microglial ATG5 is essential to maintain postnatal hippocampal neurogenesis in a mouse model of AD.
- Our findings further support the notion that ATG5 in microglia supports NSC health and may prevent neurodegeneration.
Why it matters
In a 5×FAD mouse model, conditional knockout of Atg5 in microglia inhibited postnatal neurogenesis in the dentate gyrus of the hippocampus but not in the subventricular zone, and this protection of neurogenesis by Atg5 in microglia was only observed in female Alzheimer mice. Depleting ATG5-deficient microglia with a CSF1R antagonist restored hippocampal neurogenesis, but these are animal findings and do not establish a treatment, cure, or prevention for human Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Autophagy) |
| Journal's citation record | 2 / 4 | Autophagy: journal h-index 240 (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 | 2024 — 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 47 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 11.8 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 3 / 6 | Cited 3.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 47 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Chenran Wang: h-index 20 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Cincinnati: institution h-index 918 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37915255) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 43 / 100 | — |
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Read the original
- DOI: 10.1080/15548627.2023.2277634
- PubMed: 37915255
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Tang, X., Walter, E., Wohleb, E., Fan, Y., & Wang, C. (2024). ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease. Autophagy. https://doi.org/10.1080/15548627.2023.2277634
Vancouver
Tang X, Walter E, Wohleb E, Fan Y, Wang C. ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease. Autophagy. 2024. doi:10.1080/15548627.2023.2277634. PMID: 37915255.
BibTeX
@article{tang2024-37915255,
author = {Tang, X. and Walter, E. and Wohleb, E. and Fan, Y. and Wang, C.},
title = {{ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease}},
journal = {Autophagy},
year = {2024},
doi = {10.1080/15548627.2023.2277634},
pmid = {37915255},
url = {https://doi.org/10.1080/15548627.2023.2277634}
}
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