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Human multiscale transcriptomics identifies the NLRP3 inflammasome as a convergent druggable target in Alzheimer’s disease: validation with dimethyl itaconate in 5xFAD mice
Kim N, Jeong DS, Lee Y, Oh C.. Research Square, 2026-10-07
Topic: Inflammation, microglia and astrocytes
Neuroinflammation is a hallmark of Alzheimer’s disease (AD); however, which neuroinflammatory effectors are consistently altered across independent human cohorts, brain regions, and microglial states—and can be engaged by available compounds—remains incompletely defined. Here, we integrated bulk transcriptomic data from 462 human AD brain samples across four independent cohorts, comprising 61,466 nuclei profiled by single-nucleus RNA-seq, to demonstrate that the NLRP3/ASC inflammasome represents a convergent therapeutic target supported by multiple molecular modalities. Neuroinflammatory pathways were consistently enriched across cohorts. Meta-analysis revealed significant upregulation of inflammasome-related genes, including GSDMD (log₂FC = 0.72; pooled p = 5.4 × 10 -5 ), PYCARD , and CASP1 ; GSDMD expression was highest at Braak stage VI, consistent with progressive engagement of the pyroptotic effector arm in advanced AD. Cell state–resolved single-nucleus analysis further showed that the proportion of inflammasome-high nuclei was higher in disease-associated microglia (DAM) from AD donors, although this difference was not detectable when all microglia were analyzed together. To evaluate the therapeutic relevance of this pathway, we treated 5xFAD mice with dimethyl itaconate (DI), a membrane-permeable inhibitor of NLRP3 signaling. DI treatment was associated with trends toward improved spatial working memory and reduced fibrillar amyloid deposition, and it broadly reversed neuroinflammatory and DAM-associated transcriptional signatures, including those of Pycard and Gsdmd , in bulk brain RNA-seq. Together, these findings support the NLRP3/ASC inflammasome pathway as a convergent neuroinflammatory target in AD and show that DI attenuates the corresponding neuroinflammatory transcriptional program in vivo, providing a translational rationale for immunometabolic therapeutic strategies in AD.
Key findings
- Meta-analysis revealed significant upregulation of inflammasome-related genes, including GSDMD (log₂FC = 0.72; pooled p = 5.4 × 10 -5 ), PYCARD , and CASP1 ; GSDMD expression was highest at Braak stage VI, consistent with progressive engagement of the pyroptotic effector arm in advanced AD.
- Cell state–resolved single-nucleus analysis further showed that the proportion of inflammasome-high nuclei was higher in disease-associated microglia (DAM) from AD donors, although this difference was not detectable when all microglia were analyzed together.
- DI treatment was associated with trends toward improved spatial working memory and reduced fibrillar amyloid deposition, and it broadly reversed neuroinflammatory and DAM-associated transcriptional signatures, including those of Pycard and Gsdmd , in bulk brain RNA-seq.
- Together, these findings support the NLRP3/ASC inflammasome pathway as a convergent neuroinflammatory target in AD and show that DI attenuates the corresponding neuroinflammatory transcriptional program in vivo, providing a translational rationale for immunometabolic therapeutic strategies in AD.
Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 47 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size and effect reported 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 29 of the 62 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” 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 | Laboratory or animal study (title names “5xfad”) — scores zero |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| 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 | 29 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 62 points we could judge it on is 47 out of 100. |
| Total | 47 / 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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APA 7th
Kim, N., Jeong, D. S., Lee, Y., & Oh, C. (2026). Human multiscale transcriptomics identifies the NLRP3 inflammasome as a convergent druggable target in Alzheimer’s disease: validation with dimethyl itaconate in 5xFAD mice. Research Square. https://doi.org/10.21203/rs.3.rs-11103693/v1
Vancouver
Kim N, Jeong DS, Lee Y, Oh C. Human multiscale transcriptomics identifies the NLRP3 inflammasome as a convergent druggable target in Alzheimer’s disease: validation with dimethyl itaconate in 5xFAD mice. Research Square. 2026. doi:10.21203/rs.3.rs-11103693/v1.
BibTeX
@article{kim2026-376fe0f8,
author = {Kim, N. and Jeong, D. S. and Lee, Y. and Oh, C.},
title = {{Human multiscale transcriptomics identifies the NLRP3 inflammasome as a convergent druggable target in Alzheimer’s disease: validation with dimethyl itaconate in 5xFAD mice}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11103693/v1},
url = {https://doi.org/10.21203/rs.3.rs-11103693/v1}
}