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A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
Liu L, Ding L, Rovere M, Wolfe MS, Selkoe DJ.. The Journal of cell biology, 2019-01-09
Topic: Disease mechanisms in lab and animal studies
Intramembrane proteolysis of transmembrane substrates by the presenilin-γ-secretase complex is preceded and regulated by shedding of the substrate's ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer's disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer's-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1-γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
Key findings
- BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain.
- An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios.
- The isolated complex responded properly to γ-secretase modulators.
- Alzheimer's-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells.
- Thus, Aβ is generated from holo-APP by a BACE1-γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
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Study details
- Evidence strengthLow
How this study scored 41/100
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 and multi-centre collaboration, so those were left out: it earned 24 of the 58 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of cell biology) |
| 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 | 2 / 5 | 2019 — within 10 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 30626721) |
| Free to read | 2 / 2 | Free to read |
| Points | 24 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 24 of the 58 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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APA 7th
Liu, L., Ding, L., Rovere, M., Wolfe, M. S., & Selkoe, D. J. (2019). A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. The Journal of cell biology. https://doi.org/10.1083/jcb.201806205
Vancouver
Liu L, Ding L, Rovere M, Wolfe MS, Selkoe DJ. A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. The Journal of cell biology. 2019. doi:10.1083/jcb.201806205. PMID: 30626721.
BibTeX
@article{liu2019-30626721,
author = {Liu, L. and Ding, L. and Rovere, M. and Wolfe, M. S. and Selkoe, D. J.},
title = {{A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor}},
journal = {The Journal of cell biology},
year = {2019},
doi = {10.1083/jcb.201806205},
pmid = {30626721},
url = {https://doi.org/10.1083/jcb.201806205}
}