. NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.


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  1. This paper takes the field closer to NLRP3 as a target for a therapeutic intervention in AD. The previous data from Michael Heneka's lab showing a role for NLRP3 in amyloid seeding already suggested it as a target (Venegas et al., 2017). The implication in this paper that IL-1β promotes tau pathology is consistent with previous work from Bruce Lamb’s lab and our own data (Bhaskar et al., 2010; Mancuso et al., 2019).


    . Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017 Dec 20;552(7685):355-361. PubMed.

    . Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.

    . CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264. PubMed.

    View all comments by Hugh Perry
  2. The paper by Ising et al. is a very important contribution to defining the deleterious roles of microglial activation in promoting tau pathology. It adds to these authors’ prior data finding analogous influences of inflammasomes upon amyloid pathology in mouse models. Perhaps a key element is the indication that some of amyloid's influence upon tau pathology is mediated by inflammasome-dependent processes. Certainly this would elevate inhibition of inflammasome activity as a drug target for testing in Alzheimer's.

    There are a number of key questions which follow from this work. As yet, it has not been demonstrated in humans when the innate immune system activation begins in the sequence of presymptomatic events leading to Alzheimer's dementia. These results would predict that at least a major increase would be expected after amyloid deposition and before tau deposition.

    A second question regards how the inflammasome influences phagocytosis. It appears that under some activation states, microglia can clear amyloid deposits. How the activation of the inflammasome interacts with these beneficial outcomes of microglial activation is very important to understand.

    A final surprise is that aging to 11 months results in changes in microglial gene expression that are similar in transgenic-tau-depositing mice and non-transgenic mice. This is especially surprising since an 11-month-old mouse is a middle-aged one, not an aged one. Given the concept that part of the effects of aging that contribute to AD might be senescence of beneficial microglial functions, learning how the senescent condition influence the inflammasome is critical.

    Excellent and convincing work by the Heneka group.

    View all comments by Dave Morgan
  3. Alzheimer’s disease is characterized by extracellular deposition of Aβ and intraneuronal accumulation of hyperphosphorylated tau protein. Previous studies showed that dementia correlates well with tau, but not with Aβ burden, indicating that tau aggregation might be the strongest driver of disease progression. However, amyloid pathology initiates decades before the first clinical symptoms of dementia, suggesting that Aβ, in combination with other factors, may eventually trigger tau pathology and neurodegeneration. This led to a very basic question: What is the connection between Aβ and tau, and how do they mutually affect each other?

    This latest work by Ising and colleagues sheds some light on this dilemma. The same group had previously demonstrated that the inflammasome, a protein complex leading to the production of the inflammatory cytokine IL1β, is activated by Aβ (Heneka et al., 2013). Additionally, inflammasome components can be released into the extracellular environment, where they facilitate Aβ deposition, thus amplifying amyloid pathology (Venegas et al., 2017). In the brain, the inflammasome is expressed in microglia, which represent the main source of IL1β during brain diseases.

    With the present work, Ising and colleagues show that the inflammasome is active in the brains of patients with frontotemporal dementia and Alzheimer’s disease. The same findings were replicated in a transgenic mouse model developing tau pathology with age. Next, the authors assessed tau pathology in the same mouse model, but deficient for crucial components of the inflammasome complex (namely NLRP3 and ASC). Interestingly, inflammasome-deficient mice were significantly protected, and displayed reduced tau burden and improved memory skills.

    Ising and colleagues provide evidence that mice lacking the inflammasome fail to induce the protein kinase CaMKII-α, which plays a critical role in tau hyperphosphorylation and aggregation. By contrast, microglia-derived IL1β increases the levels of CaMKII-α and promotes tau aggregation in neurons. Similarly, tau monomers and oligomers, but not fibrils, induce IL-1β release in microglia. Lastly, the authors show that Aβ worsens tau deposition in mouse in an inflammasome-dependent manner.

    Altogether, these data elucidate a novel link between Aβ and tau pathology. Aβ accumulation triggers inflammasome activation in microglia, with ensuing release of IL1β, which in turns activates kinases in neurons that induce tau hyperphosphorylation and aggregation. Future studies will determine whether inflammasome could be a promising therapeutic target for Alzheimer’s and tau pathologies.  


    . NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.

    . Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017 Dec 20;552(7685):355-361. PubMed.

    View all comments by Simone Brioschi
  4. This manuscript by the Heneka lab dissects the influence of inflammasome activation on tau pathology in a mouse model of tauopathy. The notion that exacerbated inflammatory responses can accelerate tau pathology ties in with previous reports indicating that microglia may be necessary for neurodegeneration associated with tau aggregation (Shi et al., 2019). This study adds to a vast body of literature suggesting that dampening inflammation and/or the release of proinflammatory cytokines can ameliorate deficits in neuronal activity and cognitive decline in various mouse models of neurodegenerative diseases (Prokop et al., 2019).

    As they have previously shown that inflammasome activation is also associated with Aβ aggregation (Heneka et al., 2013; Venegas et al., 2017),  the authors come full circle to put Aβ and inflammation upstream of tau phosphorylation in an injection model of amyloidosis. This paper provides further evidence for the amyloid cascade hypothesis (Hardy, 2017) of Alzheimer’s disease (AD) pathogenesis, integrating Aβ deposition, tau pathology, and immune response into a complex picture of cascading events ultimately leading to neurodegeneration.

    While this study provides important insight into the role of inflammatory processes in progression of tau pathology, there are some caveats with broadening the findings of this study.

    First, the mouse model used relies on overexpression of a tau variant carrying two pathogenic tau mutations, and does not necessarily reflect the speed and pattern of tau aggregation observed in sporadic AD. Studies of the impact of inflammasome inactivation in other mouse models of tauopathy expressing wild-type tau and exhibiting longer progression times will be very informative moving forward.

    Second, the effect of inflammasome inactivation was achieved using knockout animal models, which often develop compensatory signaling pathways due to the permanent absence of the deleted key messenger proteins. Studies with inflammasome inhibitors as treatments will therefore be a very important next step in validating this pathway for potential therapeutic interventions.

    Third, most of the current genetic risk variants in microglia-associated genes are partial loss-of-function variants, making an important argument for immune activation, rather than immune inhibition as a potential therapeutic strategy moving forward (Golde, 2019). This only underscores the complexity of the system, where it will be of utmost importance to find the right balance between activation and inhibition of immune responses to address the human AD condition.


    . Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    . Neuroimmune interactions in Alzheimer's disease-New frontier with old challenges?. Prog Mol Biol Transl Sci. 2019;168:183-201. Epub 2019 Oct 24 PubMed.

    . NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.

    . Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017 Dec 20;552(7685):355-361. PubMed.

    . The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the "amyloid cascade hypothesis". FEBS J. 2017 Apr;284(7):1040-1044. PubMed.

    . Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders. Neuron. 2019 Mar 20;101(6):1003-1015. PubMed.

    View all comments by Todd E. Golde
  5. "This implies therapeutic interventions will have to be tailored to the disease stage."

    Until such therapeutic agents are actually available, advising at-risk patient populations to minimize their exposure to toxic agents, including diesel exhaust, that have the potential to activate microglia and promote NLRP3 inflammasome activation seems prudent, and does no harm.


    . Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms. Neurotoxicology. 2016 Sep;56:204-214. Epub 2016 Aug 16 PubMed.

    . Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease. Part Fibre Toxicol. 2017 Aug 30;14(1):35. PubMed.

    . PM2.5 exposure aggravates oligomeric amyloid beta-induced neuronal injury and promotes NLRP3 inflammasome activation in an in vitro model of Alzheimer's disease. J Neuroinflammation. 2018 May 2;15(1):132. PubMed.

    . Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation. 2011 Aug 24;8:105. PubMed.

    View all comments by Marcia Ratner

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  1. Microglia Inflammasome Stokes Tau Phosphorylation, Tangles


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