Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels
Lee CY, Tse W, Smith JD, Landreth GE.. The Journal of biological chemistry, 2011-11-30
Topic: Brain proteins, microglia and lab models
Allelic variation in the apolipoprotein E (APOE) gene is the major risk factor of sporadic Alzheimer disease. ApoE is the primary cholesterol carrier in the brain. Previously, we demonstrated that intracellular degradation of β-amyloid (Aβ) peptides by microglia is dramatically enhanced in the presence of apoE. However, the molecular mechanisms subserving this effect remain unknown. This study reports a mechanistic link between apoE-regulated cholesterol homeostasis and Aβ degradation. We demonstrate that promoting intracellular Aβ degradation by microglia is a common feature of HDL apolipoproteins, including apoE and apoA-I. This effect was not dependent on the direct interaction of apoE and Aβ. Regulation of Aβ degradation was achieved by solely manipulating cellular cholesterol levels. The expression and the activity of Aβ degrading enzymes, however, were not regulated by cholesterol. We observed that reducing cellular cholesterol levels by apoE resulted in faster delivery of Aβ to lysosomes and enhanced degradation. Moreover, apoE facilitated the recycling of Rab7, a small GTPase responsible for recruiting the motor complex to late endosomes/lysosomes. These data indicate that faster endocytic trafficking of Aβ-containing vesicles in the presence of apoE resulted from efficient recycling of Rab7 from lysosomes to early endosomes. Thus, apoE-induced intracellular Aβ degradation is mediated by the cholesterol efflux function of apoE, which lowers cellular cholesterol levels and subsequently facilitates the intracellular trafficking of Aβ to lysosomes for degradation. These findings demonstrate a direct role of cholesterol in the intracellular Aβ degradation.
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APA 7th
Lee, C. Y., Tse, W., Smith, J. D., & Landreth, G. E. (2012). Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m111.295451
Vancouver
Lee CY, Tse W, Smith JD, Landreth GE. Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels. The Journal of biological chemistry. 2012. doi:10.1074/jbc.m111.295451. PMID: 22130662.
BibTeX
@article{lee2012-22130662,
author = {Lee, C. Y. and Tse, W. and Smith, J. D. and Landreth, G. E.},
title = {{Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels}},
journal = {The Journal of biological chemistry},
year = {2012},
doi = {10.1074/jbc.m111.295451},
pmid = {22130662},
url = {https://doi.org/10.1074/jbc.m111.295451}
}
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Key findings
- Previously, we demonstrated that intracellular degradation of β-amyloid (Aβ) peptides by microglia is dramatically enhanced in the presence of apoE.
- We observed that reducing cellular cholesterol levels by apoE resulted in faster delivery of Aβ to lysosomes and enhanced degradation.
- These data indicate that faster endocytic trafficking of Aβ-containing vesicles in the presence of apoE resulted from efficient recycling of Rab7 from lysosomes to early endosomes.
- These findings demonstrate a direct role of cholesterol in the intracellular Aβ degradation.
Why it matters
In laboratory work, apoE helped microglia break down amyloid-beta by lowering cellular cholesterol and speeding delivery of amyloid-beta to lysosomes. This is a mechanistic, cell-level finding and does not establish any treatment or prevention in people.
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Study details
- Evidence strengthLow
How this study scored 47/100
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 (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (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 | 1 / 5 | 2012 — within 20 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 | 5 / 7 | Cited 178 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 11.1 citations a year over 16 year(s) since 2012 |
| Impact for its field and year | 3 / 6 | Cited 7.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 11 other studies in this library |
| Still being cited | 2 / 4 | Cited 39 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Gary E. Landreth: h-index 101 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Case Western Reserve University: institution h-index 1,159 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22130662) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 47 / 100 | — |
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