New mechanism of the onset of Alzheimer's disease in Nature: inflammatory small body activation drives Tau pathological changes.

Department of neurodegenerative diseases and geriatric psychology, University Hospital of Bonn, Bonn, Alzheimer's disease is the main Alzheimer's disease, which is characterized by the accumulation of plaques amyloid - β, the accumulation of hyperphosphorylated tau in neurofibrillary tangles, and neuroinflammation, which jointly lead to neurodegeneration and cognitive decline.NLRP3 inflammasome aggregates in activated microglia, resulting in cleavage, release and maturation of caspase-1 and downstream interleukin-1 β.NLRP3 inflammasome has been proved to be essential.the development and progression of amyloid - β in mouse model diseases are not clear.here, we found that the loss of NLRP3 inflammasome function can reduce tau phosphorylation and aggregation by regulating tau phosphatase and kinase.tau activated NLRP3 inflammatory corpuscles and injected brain homogenate containing amyloid fibrillary protein to induce tau pathology in a NLRP3 dependent manner.these data confirm the important role of microglia and NLRP3 inflammasome activation in the pathogenesis of Alzheimer's disease, and support the amyloid cytology hypothesis of Alzheimer's disease, suggesting that neurofibrillary tangles develop into downstream pathways of amyloid beta induced microglia activation.schematic diagram of the role of inflammatory corpuscles in neurodegenerative diseases inflammatory corpuscle (inflammasome) is a polyprotein complex composed of sensors, adaptors and proaspase-1.the assembly of inflammatory corpuscles is a response to pathogen related molecular model (PAMP) and injury related molecular model (damp).inflammatory corpuscles cause caspase-1 to self shear and activate, then cleave pro-il-1 β and pro-il-18 to form mature IL-1 β, IL-18. Activated caspase-1 can also cleave gasdemind, leading to a special cell death, called pyroptosis.gene mutations that encode components of inflammatory bodies are associated with many inflammatory diseases. Studies in the past decade have highlighted the importance of appropriate activation of inflammatory bodies in homeostasis and disease pathogenesis.all members of the NLR protein family assembled by inflammatory bodies contain a central nucleotide binding domain (NBD), and most members have a variable N-terminal domain and a C-terminal LRR domain.according to the presence of N-terminal pyrin domain (PYD) or card, the family is further divided into nlrp or nlrc receptors.the NLR gene of human and mouse encodes 22 NLRs and 34 NLRs respectively.among them, nlrp1, NLRP3 and nlrc4 are platforms that can induce the formation of inflammatory bodies and activate caspase-1.nlrp12, nlrp6 and nlrp9b are also considered to be involved in inflammatory corpuscles, but their roles have not been well confirmed.inflammatory corpuscle assembly requires the same type of card card card or PYD PYD interaction, and both PYD and card domains can be induced to oligomerize, which is the basis of inflammatory body assembly.when the ligand is detected, the sensor is released from the inhibited state and aggregates, and ASCs nucleate by homotype interaction between their pyds.next, ASCs recruit proase-1 through their card domain interactions. The synthesized polyinflammatory complex contains sensors, adaptors and enzymes.the assembly of nlrp 3, aim 2 and pyrin inflammatory bodies is strictly dependent on the adapter ASC.on the contrary, nlrp1 and nlrc4 have a card domain and can recruit caspase-1 directly.nlrp1 and nlrc 4 can induce inflammatory body assembly and cell death independently of ASC. However, ASC still promoted the effective treatment of IL-1 β and IL-18.because inflammatory corpuscle assembly requires homotype card card and PYD PYD interaction, some pure PYD proteins (POPs) and pure card proteins (CoPS) can be used as the dominant negative regulatory factors of inflammatory body assembly.nlpr3nlrp3 is the sensor of NLRP3 inflammatory bodies (adapter ASC (pycard) and effector molecule (caspase 1)), which is composed of N-terminal PYD domain, central NBD domain and C-terminal LRR domain.nlrp 3 mutations have been observed in autoimmune inflammatory diseases, such as freezing related periodic syndrome (CAPS) characterized by rashes and fever.nlrp 3 was finally found to be a NLR, which can form inflammatory bodies and sense a large number of infectious and endogenous damps (including microbial cell wall components, nucleic acids, porotoxin, environmental crystallizers (such as silica) and endogenous molecules, including ATP and uric acid crystals).when NLRP3 inflammasome reacts to a large number of damps, it can sense the common cell distress signals (changes in cell volume, lysosome disruption, ROS production, K efflux and Ca2 + signals) caused by these molecules, rather than directly interacting with all of these signal triggers.schematic diagram of inflammatory corpuscle activation and signal pathway 02jess automatic quantitative Western blot technology in this paper, Jess detection or collection of conditioned medium for neural experiments, 2 million microglia or 600, was used to detect or collect the secretory caspase-1 and its cleavage in conditioned medium, 000 microglia per well were plated in a 6-wellplate.caspase -1secretion by using a Jess system (ProteinSimple). Here, samples were run undiluted on a 12–230-kDa separation module according to the manufacturer’s instructions and detection was achieved by using a caspase-1 antibody (Adipogen) at 1:50. Data were analysed with Compass softwareResults: Jess based analysis of conditioned medium of LPS + tau wild type treated wild type microglia stabilized for caspase-1, Asc–/– and Nlrp3–/– microglia primed with LPS and treated with the indicated forms of tau P301S. LPS/ATP-treated wild-type microglia served as positive control. Samples were stained for caspase-1.