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Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease
Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA et al.. Nature, 2023-05-31
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4-7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., et al. (2023). Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature. https://doi.org/10.1038/s41586-023-06120-6
Vancouver
Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, et al. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature. 2023. doi:10.1038/s41586-023-06120-6. PMID: 37258678.
BibTeX
@article{depp2023-37258678,
author = {Depp, C. and Sun, T. and Sasmita, A. O. and Spieth, L. and Berghoff, S. A. and Nazarenko, T. and Overhoff, K. and Steixner-Kumar, A. A. and others},
title = {{Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease}},
journal = {Nature},
year = {2023},
doi = {10.1038/s41586-023-06120-6},
pmid = {37258678},
url = {https://doi.org/10.1038/s41586-023-06120-6}
}
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
- Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2,3 .
- Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers.
Why it matters
In mouse models of Alzheimer's disease, damaged myelin — the insulating sheath around nerve fibres — led to more build-up of amyloid, the protein that forms plaques. The study reports that the machinery that produces amyloid accumulated in swollen nerve fibres, and that immune cells which normally surround plaques appeared to be drawn away to the nearby myelin damage instead. This is animal research into why ageing might raise risk; it tested no treatment and says nothing yet about people.
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Study details
- Evidence strengthLow
How this study scored 65/100
Published in a top-tier 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 | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (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 | 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 | 6 / 7 | Cited 480 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 96.0 citations a year over 5 year(s) since 2023 |
| Impact for its field and year | 6 / 6 | Cited 68.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 other studies in this library |
| Still being cited | 4 / 4 | Cited 422 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Klaus‐Armin Nave: h-index 114 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 37258678) |
| Free to read | 2 / 2 | Free to read |
| Total | 65 / 100 | — |
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