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ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology
Thakur K, Péladeau C, Hewitt M, Baumann K, Cai D, Woulfe JM, Tomlinson JJ, Schlossmacher MG et al.. bioRxiv, 2026-10-10
Topic: Inflammation, microglia and astrocytes
Neuroinflammation is a hallmark of several chronic neurodegenerative disorders, including Parkinson’s disease (PD) and other synucleinopathies, and is closely associated with microglial activation. The inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) undergoes oligomerization upon inflammasome activation, resulting in the formation of ASC specks. These structures are recognized by microglia as damage-associated molecular patterns (DAMPs), thereby promoting inflammatory signaling. Recent studies have demonstrated that extracellular ASC specks associate with amyloid-β (Aβ), and that uptake of ASC-Aβ composites by microglia amplifies pro-inflammatory responses. Although ASC specks have also been shown to potentiate α-synuclein (αSyn) preformed fibril-induced pathology, their interaction with monomeric αSyn and their effects on inflammasome activation remain poorly understood. Here, we co-stimulated murine SIM-A9 microglia with ASC-αSyn assemblies and evaluated their effects on NLRP3 inflammasome activation. Electron microscopy revealed a close association between ASC fibrils and αSyn monomers. Exposure of microglia to ASC-αSyn enhanced NLRP3 inflammasome activation, as evidenced by increased ASC speck formation, caspase-1 activation, and secretion of IL-1β and IL-18, when compared to ASC or αSyn alone. In addition, immunohistochemical analyses of post mortem brain tissue from patients with dementia with Lewy bodies demonstrated ASC expression in regions exhibiting αSyn pathology and showed ASC co-localization with αSyn within Lewy bodies. Collectively, these findings identify ASC-αSyn assemblies as potent amplifiers of NLRP3 inflammasome signaling and suggest a mechanism through which they may contribute to sustained neuroinflammation in synucleinopathies.
Key findings
- Neuroinflammation is a hallmark of several chronic neurodegenerative disorders, including Parkinson’s disease (PD) and other synucleinopathies, and is closely associated with microglial activation.
- Recent studies have demonstrated that extracellular ASC specks associate with amyloid-β (Aβ), and that uptake of ASC-Aβ composites by microglia amplifies pro-inflammatory responses.
- Electron microscopy revealed a close association between ASC fibrils and αSyn monomers.
- Exposure of microglia to ASC-αSyn enhanced NLRP3 inflammasome activation, as evidenced by increased ASC speck formation, caspase-1 activation, and secretion of IL-1β and IL-18, when compared to ASC or αSyn alone.
- In addition, immunohistochemical analyses of post mortem brain tissue from patients with dementia with Lewy bodies demonstrated ASC expression in regions exhibiting αSyn pathology and showed ASC co-localization with αSyn within Lewy bodies.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. 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 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 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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
Thakur, K., Péladeau, C., Hewitt, M., Baumann, K., Cai, D., Woulfe, J. M., et al. (2026). ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology. bioRxiv. https://doi.org/10.64898/2026.10.02.756339
Vancouver
Thakur K, Péladeau C, Hewitt M, Baumann K, Cai D, Woulfe JM, et al. ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology. bioRxiv. 2026. doi:10.64898/2026.10.02.756339.
BibTeX
@article{thakur2026-ca6358d7,
author = {Thakur, K. and Péladeau, C. and Hewitt, M. and Baumann, K. and Cai, D. and Woulfe, J. M. and Tomlinson, J. J. and Schlossmacher, M. G. and others},
title = {{ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.02.756339},
url = {https://doi.org/10.64898/2026.10.02.756339}
}
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