APOE4 impairs autophagy and Aβ clearance by microglial cells
Rawan Bassal, Maria Rivkin-Natan, Alon Rabinovich, Daniel Moris Michaelson, Dan Frenkel, Ronit Pinkas-Kramarski. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2025-04-01
Topic: Inflammation, microglia and astrocytes
Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.
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APA 7th
Bassal, R., Rivkin-Natan, M., Rabinovich, A., Michaelson, D. M., Frenkel, D., & Pinkas-Kramarski, R. (2025). APOE4 impairs autophagy and Aβ clearance by microglial cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. https://doi.org/10.1007/s00011-025-02016-5
Vancouver
Bassal R, Rivkin-Natan M, Rabinovich A, Michaelson DM, Frenkel D, Pinkas-Kramarski R. APOE4 impairs autophagy and Aβ clearance by microglial cells. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2025. doi:10.1007/s00011-025-02016-5. PMID: 40164781.
BibTeX
@article{bassal2025-40164781,
author = {Bassal, Rawan and Rivkin-Natan, Maria and Rabinovich, Alon and Michaelson, Daniel Moris and Frenkel, Dan and Pinkas-Kramarski, Ronit},
title = {{APOE4 impairs autophagy and Aβ clearance by microglial cells}},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
year = {2025},
doi = {10.1007/s00011-025-02016-5},
pmid = {40164781},
url = {https://doi.org/10.1007/s00011-025-02016-5}
}
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Key findings
- In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found.
- Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD.
- The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia.
- We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3.
- Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3.
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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. 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, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Inflammation research : official journal of the European Histamine Research Society ... [et al.]) |
| 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 | 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 | — / 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 | 2 / 2 | Indexed in PubMed (PMID 40164781) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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