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During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Approximately ten million people are diagnosed with dementia annually since they experience difficulties with memory and thinking skills. Since neurodegenerative diseases are diagnosed late, most of them are difficult to treat. This is due to the increased severity of the disease during the progression when neuroinflammation plays a critical role. The activation of immune cells, especially microglia, plays a crucial role in the development of neurodegenerative diseases. Molecular sensors within these microglia, such as the NLRP3 inflammasome, are activated by signals that represent the hallmarks of neurodegenerative diseases. Here, we first summarize the two activation steps of NLRP3 inflammasome activation. Furthermore, we discuss the key factors that contribute to NLRP3 inflammasome activation in the different neuroinflammatory diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The prominent NLRP3 inflammasome triggers include amyloid β and tau oligomers in AD, α-synuclein in PD, and superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43) in ALS. NLRP3 inhibitor treatment has shown promising results in several preclinical mouse models of AD, PD, and ALS. Finally, we postulate that current understandings underpin the potential for NLRP3 inhibitors as a therapeutic target in neurodegenerative diseases., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli , which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype. SIGNIFICANCE STATEMENT Acute peripheral immune stimulation has been shown to have both positive and negative effects on Aβ deposition. Improvements or worsening may be possible in acute inflammation. However, there is still no evidence of effects longer than a month after stimulation. The data are pointing to an important role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome for mediating the long-term consequences of systemic immune stimulation, which in addition turns out to be age dependent., (Copyright © 2020 the authors.)

Historically neurodegenerative diseases, Alzheimer's disease (AD) in particular, have been viewed to be primarily caused and driven by neuronal mechanisms. Very recently, due to experimental, genetic, and epidemiologic evidence, immune mechanisms have entered the central stage and are now believed to contribute significantly to risk, onset, and disease progression of this class of disorders. Although immune activation of microglial cells may over time engage various signal transduction pathways, inflammasome activation, which represents a canonical and initiating pathway, seems to be one of the first responses to extracellular β-amyloid (Aβ) accumulation. Here we review the current understanding of inflammasome activation in AD.-Venegas, C., Heneka, M. T. Inflammasome-mediated innate immunity in Alzheimer's disease.

Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline 1 . The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release 2 . Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice 3 , the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression.

Alzheimer's disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD., Competing Interests: The authors declare no conflict of interest.

Inflammation within the CNS is a major component of many neurodegenerative diseases. A characteristic feature is the generation of microglia-derived factors that play an essential role in the immune response. IL-1β is a pro-inflammatory cytokine released by activated microglia, able to exacerbate injury at elevated levels. In the presence of caspase-1, pro-IL-1β is cleaved to the mature cytokine following NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation. Growing evidence suggests that ceramide plays a critical role in NLRP3 inflammasome assembly, however, the relationship between ceramide and inflammasome activation in microglia remains unknown. Here, we investigated potential mechanistic links between ceramide as a modulator of NLRP3 inflammasome assembly and the resulting secretion of IL-1β using small bioactive enzyme stimulators and inhibitors of ceramide signaling in wild-type and apoptosis-associated speck-like protein containing a CARD knockout (ASC -/- ) primary microglia. To induce the expression of inflammasome components, microglia were primed prior to experiments. Treatment with sodium palmitate (PA) induced de novo ceramide synthesis via modulation of its synthesizing protein serine palmitoyl transferase resulting in increased IL-1β secretion in microglia. Exposure of microglia to the serine palmitoyl transferase-inhibitor l-cycloserine significantly prevented PA-induced IL-1β secretion. Application of the ceramide analogue C2 and the sphingosine-1-phosphate-receptor agonist Fingolimod (FTY720) up-regulated levels of IL-1β and cleaved caspase-1 in wild-type microglia, whereas ASC -/- microglia were unaffected. HPA-12 inhibition of ceramide transport did not affect inflammasome activation. Taken together, our findings reveal a critical role for ceramide as a positive modulator of NLRP3 inflammasome assembly and the resulting release of IL-1β., (© 2017 International Society for Neurochemistry.)

Activation of innate immunity and the assembly of microglial cells at sites of Alzheimer disease pathology has long been regarded as bystander phenomenon, which does not actively contribute to disease pathogenesis and progression. Recent data emerging from genetics, clinical imaging and animal experimentation point to an intimate and mutual interaction of innate immune mechanisms and neurodegenerative processes. NOD-like receptor (NLR) family, pyrin domain containing 3 and 1 inflammasomes, present in myeloid cells and neurons, respectively, represent key components of the innate immune reaction observed in Alzheimer patient brains. Inhibition of inflammasome activation just begins to prove beneficial and protective from cognitive deficits and neuronal death in cell culture and animal models of Alzheimer's disease, thereby opening a new avenue for therapeutic intervention., (© 2016 International Society of Neuropathology.)