Omics · study · 2026
Human multi-omics identifies the NLRP3 inflammasome as a convergent druggable target in Alzheimer's disease: validation with dimethyl itaconate in 5xFAD mice
Listed in NCBI GEO
Neuroinflammation is a hallmark of Alzheimer’s disease (AD), yet the systematic identification of pharmacologically tractable neuroinflammatory targets from large-scale human molecular datasets remains an unmet clinical need.
Description
Here we integrated bulk transcriptomic data from 462 human AD brain samples across four independent cohorts with single-nucleus RNA-seq (61,466 nuclei) to demonstrate that the NLRP3/ASC inflammasome represents a convergent therapeutic target supported across multiple molecular modalities.
Across cohorts, neuroinflammatory pathways were consistently enriched. Meta-analysis revealed significant upregulation of inflammasome-related genes, including GSDMD (log₂FC = 0.72; pooled p = 5.4× 10^(-5)), PYCARD and CASP1, while cell-type–resolved analyses identified increased expression of NLRP3, CASP1, and IL18 in microglia. Inflammasome-associated gene expression also correlated with Braak neuropathological staging.
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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 improved spatial working memory, reduced fibrillar amyloid deposition, and partially normalized neuroinflammatory transcriptional signatures in RNA sequencing. Together, these results highlight the NLRP3/ASC inflammasome as a potential therapeutic target and support further investigation of immune-metabolic modulation strategies for AD.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342347 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342347 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1507403 ncbi.nlm.nih.gov/bioproject/PRJNA1507403 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Disease 75% · RNA sequencing 75% · Sequencing 75% · Single-cell RNA sequencing 65%
Provenance · 1 source records, 11 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE342347 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:single-cell-rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |