Upregulation of NLRP3 Inflammasome in Specific Hippocampal Regions: Strengthening the Link Between Neuroinflammation and Selective Vulnerability in Alzheimer's Disease

Eliana C B Toscano; Alberto F O Justo; Michelle C A Paula; Laura B Grossi; Vitor H Neves; Renata E P Leite; Vitor R Paes; Rossana C N Melo; Ricardo Nitrini; Carlos Pasqualucci; Eduardo Ferriolli; Antonio L Teixeira; Lea T Grinberg; Claudia K Suemoto

doi:10.1007/s12035-025-04975-6

Upregulation of NLRP3 Inflammasome in Specific Hippocampal Regions: Strengthening the Link Between Neuroinflammation and Selective Vulnerability in Alzheimer's Disease

Mol Neurobiol. 2025 Apr 25. doi: 10.1007/s12035-025-04975-6. Online ahead of print.

Authors

Affiliations

¹ Laboratory of Pathology, Department of Pathology, Federal University of Juiz de Fora Medical School, Eugênio Do Nascimento, S/No.-Dom Bosco, Juiz de Fora, MG, 36038 - 330, Brazil. elianacbtoscano@gmail.com.
² Physiopathology in Aging Laboratory (LIM- 22), Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil. elianacbtoscano@gmail.com.
³ Physiopathology in Aging Laboratory (LIM- 22), Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
⁴ Laboratory of Pathology, Department of Pathology, Federal University of Juiz de Fora Medical School, Eugênio Do Nascimento, S/No.-Dom Bosco, Juiz de Fora, MG, 36038 - 330, Brazil.
⁵ Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
⁶ Department of Neurology, University of São Paulo Medical School, São Paulo, Brazil.
⁷ Division of Geriatrics, Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil.
⁸ The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, USA.
⁹ Memory and Aging Center, University of California San Francisco, San Francisco, USA.

PMID: 40281298
DOI: 10.1007/s12035-025-04975-6

Abstract

Neuroinflammation has emerged as an important mechanism in the early stages of neurodegenerative diseases. Experimental models have demonstrated the detrimental role of inflammasomes in the development of Alzheimer's disease (AD). However, neuropathological studies characterizing NLRP1 and NLRP3 pathways in AD are scarce. In addition, the possible association between inflammasome-induced neuroinflammation and clinicopathological outcomes is unclear. This study aimed to characterize the hippocampal expression of the inflammasome proteins in post-mortem samples of individuals with pure AD neuropathological change (ADNC) compared to controls from an admixed Latin American sample (n = 28 per group). We also investigated potential associations of inflammasome expression with neuropathological burden and cognitive abilities. The expression of NLRP1, NLRP3, caspase-1, ASC, gasdermin D, IL-1β, IL-18, amyloid β, and hyperphosphorylated tau (p-tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB), using immunohistochemistry and morphometry. We also performed the alignment of serial sections and 3D reconstruction of ADNC samples to verify the spatial locations of NLRP3/ASC and AD pathology across the hippocampus. We used ordinal logistic regression to investigate potential associations between inflammasome proteins and AD pathology, while linear regression assessed relationships between inflammasome and cognitive abilities. NLRP3, ASC, caspase-1, IL-1β, and IL-18 were overexpressed in CA and SUB of individuals with ADNC compared to controls. NLRP3 pathway correlated with AD pathology and CDR-SB, mainly in CA and SUB. Our results suggest that hippocampal NLRP3, but not NLRP1, inflammasome was associated with pathologic burden and cognitive impairment in AD and may contribute to the selective vulnerability to AD pathology.

Keywords: AD Pathology; Alzheimer’s Disease; Hippocampus; Inflammasome; NLRP3.

Abstract

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