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Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF
Im E, Jiang Y, Stavrides PH, Darji S, Erdjument-Bromage H, Neubert TA, Choi JY, Wegiel J et al.. Science advances, 2023-07-26
Topic: Brain proteins, microglia and lab models
Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal vacuolar (H + )-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated 682 YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr 682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr 682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr 682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Im, E., Jiang, Y., Stavrides, P. H., Darji, S., Erdjument-Bromage, H., Neubert, T. A., et al. (2023). Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF. Science advances. https://doi.org/10.1126/sciadv.adg1925
Vancouver
Im E, Jiang Y, Stavrides PH, Darji S, Erdjument-Bromage H, Neubert TA, et al. Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF. Science advances. 2023. doi:10.1126/sciadv.adg1925. PMID: 37494443.
BibTeX
@article{im2023-37494443,
author = {Im, E. and Jiang, Y. and Stavrides, P. H. and Darji, S. and Erdjument-Bromage, H. and Neubert, T. A. and Choi, J. Y. and Wegiel, J. and others},
title = {{Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF}},
journal = {Science advances},
year = {2023},
doi = {10.1126/sciadv.adg1925},
pmid = {37494443},
url = {https://doi.org/10.1126/sciadv.adg1925}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- Notably, lowering APP-βCTF Tyr 682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF.
- These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.
Why it matters
This study shows that the phosphorylated 682 YENPTY motif of APP-betaCTF binds the v-ATPase V0a1 subunit and competitively inhibits v-ATPase, disrupting lysosome function in Down syndrome fibroblasts and mouse brains. Lowering this phosphorylation restored v-ATPase and lysosome function in cells and in mice, but these are laboratory and animal findings, not a tested treatment for people.
Study details
- Evidence strengthLow
How this study scored 50/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 48 of the 96 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science advances) |
| Journal's citation record | 3 / 4 | Science Advances: journal h-index 378 (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 | 3 / 5 | 2023 — within 6 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 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 80 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.0 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 4 / 6 | Cited 11.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 3 / 4 | Cited 71 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | New York University: institution h-index 1,612 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37494443) |
| Free to read | 2 / 2 | Free to read |
| Points | 48 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 48 of the 96 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
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