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PLD3 affects axonal spheroids and network defects in Alzheimer's disease
Yuan P, Zhang M, Tong L, Morse TM, McDougal RA, Ding H, Chan D, Cai Y et al.. Nature, 2022-11-30
Topic: Disease mechanisms in lab and animal studies
The precise mechanisms that lead to cognitive decline in Alzheimer's disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction. Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer's disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner. Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3-a potential Alzheimer's-disease-associated risk gene 1 that encodes a lysosomal protein 2,3 that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer's disease, independent of amyloid removal.
Key findings
- Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3-a potential Alzheimer's-disease-associated risk gene 1 that encodes a lysosomal protein 2,3 that is highly enriched in axonal spheroids.
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Study details
- Evidence strengthLow
How this study scored 48/100
Published in a top-tier 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 28 of the 58 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| 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 | 3 / 5 | 2022 — 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 | 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 36450991) |
| Free to read | 2 / 2 | Free to read |
| Points | 28 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 28 of the 58 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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.
APA 7th
Yuan, P., Zhang, M., Tong, L., Morse, T. M., McDougal, R. A., Ding, H., et al. (2022). PLD3 affects axonal spheroids and network defects in Alzheimer's disease. Nature. https://doi.org/10.1038/s41586-022-05491-6
Vancouver
Yuan P, Zhang M, Tong L, Morse TM, McDougal RA, Ding H, et al. PLD3 affects axonal spheroids and network defects in Alzheimer's disease. Nature. 2022. doi:10.1038/s41586-022-05491-6. PMID: 36450991.
BibTeX
@article{yuan2022-36450991,
author = {Yuan, P. and Zhang, M. and Tong, L. and Morse, T. M. and McDougal, R. A. and Ding, H. and Chan, D. and Cai, Y. and others},
title = {{PLD3 affects axonal spheroids and network defects in Alzheimer's disease}},
journal = {Nature},
year = {2022},
doi = {10.1038/s41586-022-05491-6},
pmid = {36450991},
url = {https://doi.org/10.1038/s41586-022-05491-6}
}
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