Innate Immune Activation Of The NLRP3 Inflammasome Pathway Drives Tau Pathology
1 Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany
2 Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany
3 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
4 IFM Therapeutics GmbH, Bonn, Germany
5 Mitchell Center for Neurodegenerative Diseases and Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
6 Divison of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
7 University of Lille, Inserm, CHU-Lille, UMR-S 1172, "Alzheimer & Tauopathies", Labex DISTALZ, Lille, France
Alzheimer’s disease is characterized by the extracellular accumulation of amyloid beta (Aß), intraneuronal formation of neurofibrillary tangles made of hyperphosphorylated tau and activated microglial cells, the innate immune cells of the brain. Activation of microglia by Aß or other DAMPs results in the assembly of the NLRP3 inflammasome consisting of NLRP3, ASC and Caspase-1. This leads to subsequent production and secretion of inflammatory mediators including IL-1β and ASC specks. Here, we investigate a contribution of the NLRP3 inflammasome to the development and progression of tau pathology.
NLRP3 inflammasome activation was increased in fronto-temporal dementia (FTD) patients carrying a tau mutation as well as in Tau22 mice, which express human tau FTD mutations. Knockout of ASC or NLRP3 in Tau22 mice decreased levels of active tau kinases while increasing activity of phosphatase PP2A in the hippocampus. This strongly protected from accumulation of hyperphosphorylated, misfolded tau in ASC knockout and more robustly in NLRP3 knockout mice while attenuating behavioral deficits. Furthermore, loss of NLRP3 inflammasome function ameliorated Aß-induced tau pathology. In vitro, treatment of microglia with tau-containing mouse brain homogenates or recombinant tau monomers and oligomers resulted in IL-1β release in a NLRP3-dependet manner, most likely mediated via TLR4. However, the same concentration of recombinant tau fibrils did not evoke this response.
These findings are in line with the hypothesis that innate immune activation represents an important pathogenic factor for tau pathology. In Alzheimer’s disease, early Aß deposition may cause subsequent tau pathology and neuronal demise through NLRP3-mediated innate immune pathways.