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Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia
Minjie Zhang, Tongyao You, Min Guo, Yichen Zhao, Yichen Zhao, Weiwei Shen, Yanfeng Jiang, Yanfeng Jiang et al.. Journal of Nanobiotechnology, 2025-11-25
Topic: Brain proteins, microglia and lab models
Lewy body dementia (LBD), which includes Parkinson's disease dementia and dementia with Lewy bodies, is characterized by progressive cognitive decline, α-synuclein (α-Syn) aggregation, and concurrent microglial activation and neuroinflammation. The nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input, plays a key role in cognitive function and is particularly affected in LBD. Cholinergic neurons within the NBM are highly vulnerable to Lewy body pathology, yet the underlying mechanisms remain poorly understood. In this study, we employed a mouse model with PFF injections into the NBM to investigate how microglia and their exosomes influence α-Syn pathology. We found that exosomes derived from activated microglia exacerbate α-Syn deposition and cognitive deficits, whereas microglial depletion mitigates these pathological changes. In vitro, activated microglial exosomes enhanced the uptake of exogenous α-Syn by cholinergic neurons. Mechanistically, we discovered that microglial exosomes can transfer bioactive membrane receptors to neurons. Focusing on lymphocyte-activation gene 3 (LAG3), a receptor critical for α-Syn internalization, we demonstrated that LAG3 is abundant in exosomes from activated-but not resting-microglia. These exosomes deliver LAG3 to neuronal membranes via an endosomal recycling pathway, a process facilitated by elevated cholesterol content, thereby promoting α-Syn uptake. Together, these findings indicate that microglial exosomes function not only as carriers of signaling molecules but also as vectors for receptor transfer, reshaping neuronal membrane composition. Our results provide a mechanistic explanation for the heightened vulnerability of NBM cholinergic neurons in LBD and reveal a novel pathway in which LAG3-rich microglial exosomes drive neuronal α-Syn internalization, advancing our understanding of neurodegeneration and identifying potential therapeutic targets.
Key findings
- We found that exosomes derived from activated microglia exacerbate α-Syn deposition and cognitive deficits, whereas microglial depletion mitigates these pathological changes.
- Focusing on lymphocyte-activation gene 3 (LAG3), a receptor critical for α-Syn internalization, we demonstrated that LAG3 is abundant in exosomes from activated-but not resting-microglia.
- Together, these findings indicate that microglial exosomes function not only as carriers of signaling molecules but also as vectors for receptor transfer, reshaping neuronal membrane composition.
- Our results provide a mechanistic explanation for the heightened vulnerability of NBM cholinergic neurons in LBD and reveal a novel pathway in which LAG3-rich microglial exosomes drive neuronal α-Syn internalization, advancing our understanding of neurodegeneration and identifying potential therapeutic targets.
Why it matters
In a mouse model of Lewy body dementia, exosomes from activated microglia worsened alpha-synuclein buildup and cognitive deficits, while removing microglia reduced these changes. This is early animal and laboratory work on Lewy body dementia, not a treatment for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 38/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Nanobiotechnology) |
| Journal's citation record | 2 / 4 | Journal of Nanobiotechnology: journal h-index 174 (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 | 4 / 5 | 2025 — within 3 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 | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Yanxin Zhao: h-index 26 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Fudan University: institution h-index 954 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41291718) |
| Free to read | 2 / 2 | Free to read |
| Total | 38 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s12951-025-03838-5
- PubMed: 41291718
- Original source →
- Free full text: Journal of Nanobiotechnology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Zhang, M., You, T., Guo, M., Zhao, Y., Shen, W., Jiang, Y., et al. (2025). Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia. Journal of Nanobiotechnology. https://doi.org/10.1186/s12951-025-03838-5
Vancouver
Zhang M, You T, Guo M, Zhao Y, Shen W, Jiang Y, et al. Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia. Journal of Nanobiotechnology. 2025. doi:10.1186/s12951-025-03838-5. PMID: 41291718.
BibTeX
@article{zhang2025-41291718,
author = {Zhang, Minjie and You, Tongyao and Guo, Min and Zhao, Yichen and Shen, Weiwei and Jiang, Yanfeng and others},
title = {{Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia}},
journal = {Journal of Nanobiotechnology},
year = {2025},
doi = {10.1186/s12951-025-03838-5},
pmid = {41291718},
url = {https://doi.org/10.1186/s12951-025-03838-5}
}
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