Tau induces inflammasome activation and microgliosis through acetylating NLRP3

• Published in: Clinical and translational medicine Vol. 14; no. 3; pp. e1623 - n/a
• Main Authors: Zhang, Lun, Gai, Yongkang, Liu, Yushuang, Meng, Dongli, Zeng, Yi, Luo, Yong, Zhang, Huiliang, Wang, Zhuoqun, Yang, Mengzhe, Li, Yunfan, Liu, Yi, Lai, Yiwen, Yang, Jiayu, Wu, Gang, Chen, Yu, Zhu, Jingtan, Liu, Shaojun, Yu, Tingting, Zeng, Ji, Wang, Jianzhi, Zhu, Dan, Wang, Xiaochuan, Lan, Xiaoli, Liu, Rong
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2024; Wiley
• Subjects: acetylation; Alzheimer's disease; Animal cognition; Antibodies; Brain; Kinases; Laboratory animals; microglia; Neurodegeneration; NLRP3 inflammasome; Pathogenesis; Pathology; Peptides; Phosphorylation; Plasmids; Proteins; Reagents; Tauopathies; Tomography; Tauopathies; acetylation; NLRP3 inflammasome; Alzheimer's disease; microglia
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1623

Background Alzheimer's disease (AD) and related Tauopathies are characterised by the pathologically hyperphosphorylated and aggregated microtubule‐associated protein Tau, which is accompanied by neuroinflammation mediated by activated microglia. However, the role of Tau pathology in microglia activation or their causal relationship remains largely elusive. Methods The levels of nucleotide‐binding oligomerisation domain (NOD)‐like receptor pyrin domain containing 3 (NLRP3) acetylation and inflammasome activation in multiple cell models with Tau proteins treatment, transgenic mice with Tauopathy, and AD patients were measured by Western blotting and enzyme‐linked immunosorbent assay. In addition, the acetyltransferase activity of Tau and NLRP3 acetylation sites were confirmed using the test‐tube acetylation assay, co‐immunoprecipitation, immunofluorescence (IF) staining, mass spectrometry and molecular docking. The Tau‐overexpressing mouse model was established by overexpression of human Tau proteins in mouse hippocampal CA1 neurons through the adeno‐associated virus injection. The cognitive functions of Tau‐overexpressing mice were assessed in various behavioural tests, and microglia activation was analysed by Iba‐1 IF staining and [18F]‐DPA‐714 positron emission tomography/computed tomography imaging. A peptide that blocks the interaction between Tau and NLRP3 was synthesised to determine the in vitro and in vivo effects of Tau–NLRP3 interaction blockade on NLRP3 acetylation, inflammasome activation, microglia activation and cognitive function. Results Excessively elevated NLRP3 acetylation and inflammasome activation were observed in 3xTg‐AD mice, microtubule‐associated protein Tau P301S (PS19) mice and AD patients. It was further confirmed that mimics of ‘early’ phosphorylated‐Tau proteins which increase at the initial stage of diseases with Tauopathy, including TauT181E, TauS199E, TauT217E and TauS262E, significantly promoted Tau–K18 domain acetyltransferase activity‐dependent NLRP3 acetylation and inflammasome activation in HEK293T and BV‐2 microglial cells. In addition, Tau protein could directly acetylate NLRP3 at the K21, K22 and K24 sites at its PYD domain and thereby induce inflammasome activation in vitro. Overexpression of human Tau proteins in mouse hippocampal CA1 neurons resulted in impaired cognitive function, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. As a targeted intervention, competitive binding of a designed Tau–NLRP3‐binding blocking (TNB) peptide to block the interaction of Tau protein with NLRP3 inhibited the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating microglia activation and cognitive impairment in mice. Conclusions In conclusion, our findings provide evidence for a novel role of Tau in the regulation of microglia activation through acetylating NLRP3, which has potential implications for early intervention and personalised treatment of AD and related Tauopathies. • NLRP3 inflammasome is activated with increased NLRP3 acetylation in Tauopathy transgenic mice and AD patients. • Tau promotes NLRP3 acetylation and inflammasome activation dependent on K18 acetyltransferase activity domain. • Tau directly acetylates NLRP3 at K21, K22 and K24 site at its PYD domain and thereby induce inflammasome activation in vitro. • Tau overexpression in mouse hippocampal CA1 neurons induces cognitive impairment, Tau transmission to microglia and microgliosis with NLRP3 acetylation and inflammasome activation. • Competitive binding of a designed TNB peptide to block the interaction of Tau with NLRP3 inhibits the NLRP3 acetylation and downstream inflammasome activation in microglia, thereby alleviating cognitive impairment in mice.