The NLRP3 inflammasome modulates tau pathology and neurodegeneration in a tauopathy model
Open accessAbstract
An active role of neuroinflammation and the NLRP3 inflammasome in Alzheimer's disease and related tauopathies is increasingly identified, supporting NLRP3 as an interesting therapeutic target. However, its effect on tau-associated neurodegeneration, a key-process in tauopathies, remains unknown. While tau pathology and neurodegeneration are closely correlated, different tau forms may act as culprits in both characteristics and NLRP3-dependent microglial processes may differently affect both processes, indicating the need to study the role of NLRP3 in both processes concomitantly. To study the role of NLRP3 on tau pathology, prion-like propagation and tau-associated neurodegeneration we generated crosses of NLRP3 deficient mice with tauP301S (PS19) transgenic mice. In this model we studied non-seeded tau pathology and hippocampal atrophy, reminiscent characteristics of tauopathies. Tau pathology in hippocampus and cortex was significantly decreased in tau.NLRP3-/- versus tau.NLRP3+/+ mice. Importantly, tau.NLRP3-/- mice also displayed significantly decreased hippocampal atrophy, indicating a role of NLRP3 in neurodegeneration. We furthermore assessed the effect of NLRP3 deficiency on tau propagation and associated hippocampal atrophy. NLRP3 deficiency significantly decreased prion-like seeding and propagation of tau pathology, reflected in decreased tau pathology in ipsi- and contralateral hippocampus and cortex in tau.NLRP3-/- following tau seeding. Most importantly, hippocampal atrophy was significantly less in tau-seeded tau.NLRP3-/- mice at 8 months. We here demonstrate for the first time that NLRP3 activation affects tau-associated neurodegeneration and seeded and non-seeded tau pathology, hence affecting key molecular processes in tauopathies. Our data thereby provide key-information in the validation of NLRP3 inflammasome as therapeutic target for AD and related tauopathies.
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NLRP3 inflammatory vesicles actively regulate tau protein pathology and affect tau aggregation by regulating intracellular and extracellular concentrations of different forms of tau to influence tau-associated neurodegeneration.
“In microglia, nucleotide-binding oligomerisation domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammatory vesicles have been shown to actively regulate tau protein pathology and affect tau protein aggregation by regulating the intracellular and extracellular concentrations of different forms of tau protein to influence tau-protein-associated neurodegeneration [40].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [40]
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References 58 · Cited by 72
- Authors
- Stancu, I. C., Lodder, C., Botella Lucena, P., Vanherle, S., Gutiérrez de Ravé, M., Terwel, D., Bottelbergs, A., & Dewachter, I.
- Affiliations
- Hasselt University (BE)
- Department of Neurosciences, Biomedical Research Institute Hasselt University Hasselt Belgium
- Janssen (Belgium) (BE)
- Corresponding author
- Dewachter, Ilse
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2022-02-17
- Volume
- 70
- Issue
- 6
- Pages
- 1117-1132
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC9307007
- OpenAlex
- W4213114226
- Cited by
- 72
- References
- 58
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 17 · 2023: 12 · 2022: 7
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Glia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Document Server@UHasselt (UHasselt) (submittedVersion, cc-by-nc-nd)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- Funders
- Fonds Wetenschappelijk Onderzoek (1259621N, G0C6819N)
- Smithsonian Astrophysical Observatory
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- NLRP3 inflammasome, tau pathology, tauopathy, neuroinflammation, tau seeding, hippocampal atrophy, Alzheimer's disease, microglia, therapeutic target
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Mice, Transgenic, tau Proteins, Tauopathies, Mice, Inflammasomes
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