Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms
Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H, Bu G.. The Journal of biological chemistry, 2012-11-06
Topic: Brain proteins, microglia and lab models
Aggregation of amyloid-β (Aβ) peptides leads to synaptic disruption and neurodegeneration in Alzheimer disease (AD). A major Aβ clearance pathway in the brain is cellular uptake and degradation. However, how Aβ traffics through the endocytic pathway and how AD risk factors regulate this event is unclear. Here we show that the majority of endocytosed Aβ in neurons traffics through early and late endosomes to the lysosomes for degradation. Overexpression of Rab5 or Rab7, small GTPases that function in vesicle fusion for early and late endosomes, respectively, significantly accelerates Aβ endocytic trafficking to the lysosomes. We also found that a portion of endocytosed Aβ traffics through Rab11-positive recycling vesicles. A blockage of this Aβ recycling pathway with a constitutively active Rab11 mutant significantly accelerates cellular Aβ accumulation. Inhibition of lysosomal enzymes results in Aβ accumulation and aggregation. Importantly, apolipoprotein E (apoE) accelerates neuronal Aβ uptake, lysosomal trafficking, and degradation in an isoform-dependent manner with apoE3 more efficiently facilitating Aβ trafficking and degradation than apoE4, a risk factor for AD. Taken together, our results demonstrate that Aβ endocytic trafficking to lysosomes for degradation is a major Aβ clearance pathway that is differentially regulated by apoE isoforms. A disturbance of this pathway can lead to accumulation and aggregation of cellular Aβ capable of causing neurotoxicity and seeding amyloid.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Li, J., Kanekiyo, T., Shinohara, M., Zhang, Y., LaDu, M. J., Xu, H., et al. (2012). Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m112.420224
Vancouver
Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H, et al. Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. The Journal of biological chemistry. 2012. doi:10.1074/jbc.m112.420224. PMID: 23132858.
BibTeX
@article{li2012-23132858,
author = {Li, J. and Kanekiyo, T. and Shinohara, M. and Zhang, Y. and LaDu, M. J. and Xu, H. and Bu, G.},
title = {{Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms}},
journal = {The Journal of biological chemistry},
year = {2012},
doi = {10.1074/jbc.m112.420224},
pmid = {23132858},
url = {https://doi.org/10.1074/jbc.m112.420224}
}
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 names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- Overexpression of Rab5 or Rab7, small GTPases that function in vesicle fusion for early and late endosomes, respectively, significantly accelerates Aβ endocytic trafficking to the lysosomes.
- A blockage of this Aβ recycling pathway with a constitutively active Rab11 mutant significantly accelerates cellular Aβ accumulation.
- Inhibition of lysosomal enzymes results in Aβ accumulation and aggregation.
- Taken together, our results demonstrate that Aβ endocytic trafficking to lysosomes for degradation is a major Aβ clearance pathway that is differentially regulated by apoE isoforms.
Why it matters
In this laboratory study, amyloid-β taken up by neurons trafficked to lysosomes for degradation, and apolipoprotein E accelerated this uptake, trafficking, and degradation in an isoform-dependent manner, with apoE3 more efficient than apoE4. These findings describe a possible clearance pathway and how apoE isoforms differ, but they are early laboratory work and do not show a treatment or prevention for Alzheimer's disease 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 randomized / 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 177 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 | 4 / 6 | Cited 9.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 2 / 4 | Cited 28 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Guojun Bu: h-index 120 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Illinois Chicago: institution h-index 918 (OpenAlex) |
| Multicenter collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23132858) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 47 / 100 | — |
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