Abstract
Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia1,2. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events3. However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3−/− or Casp1−/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
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Change history
30 January 2013
Minor corrections were made to Fig. 2d and the legend to Fig. 3.
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Acknowledgements
This work was funded by the Dana Foundation (E.L.), the National Institutes of Health (E.L., D.T.G.) and the Deutsche Forschungsgemeinschaft (E.L., M.T.H.). We thank G. Nuñez and V. M. Dixit for providing anti-caspase-1 Abs. We thank B. De Strooper and L. Serneels for the BACE1 knockout mice and discussion. We also thank H. Jacobsen for the BACE1 transgenic mice.
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M.T.H, M.P.K, A.S., A.D., S.S., A.V.-S., A.G., D.A., A.R., T.T. and E.L. performed experiments and analysed data, E.G. provided human samples and analysed data, A.H. was involved in study design and analysed data, E.L., M.T.H., M.K. and D.T.G. designed the study and wrote the paper. All authors discussed results and commented on the manuscript.
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Heneka, M., Kummer, M., Stutz, A. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013). https://doi.org/10.1038/nature11729
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DOI: https://doi.org/10.1038/nature11729
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Chris Exley
I wonder, is it wholly a coincidence that we have been using Al-based adjuvants (known activators of the inflammasome) for about 100 years!?
Claudiu Bandea
A new (unexpected) paradigm on the role of innate immunity in neurodegenerative diseases
The study by Heneka et al. (1), showing that NLRP3 inflammasome is activated in Alzheimer's disease (AD) and contributes to pathology in APP/PS1 mice, is a significant addition to the abundant evidence that the innate immune system is involved in AD (2). However, similar to hundreds of other important AD studies published in the last few decades, without integrating the results in a productive theory that explains the etiology of AD, this study is unlikely to lead to a breakthrough in the development of successful preventive and therapeutic approaches.
Unfortunately, the protein misfolding theory and the prion hypothesis, which for decades have directed most of the thinking and research on AD and other neurodegenerative diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Creutzfeldt-Jacob disease (JCD), have yet to integrate the large quantity of data and observation in a productive scientific platform for understanding the etiology of these diseases. As recently proposed (3, 4), there is increasing evidence that both of these working hypotheses are flawed and have misdirected the research and the interpretation of data and observations in these fields.
For example, in the context of the protein misfolding theory, the AD, PD, HD, ALS and CJD have been classified as protein misfolding diseases and thought to be caused by the misfolding of primary proteins implicated in these diseases: amyloid-beta and tau in AD, alpha-synuclein in PD, huntingtin in HD, TDP-43 in ALS, and prion protein in CJD. On the other hand, in the context of the prion hypothesis, this misfolding activity is caused by replicating prions, or prion-like entities, which are considered the pathogens causing these diseases (reviewed in 5). Therefore, according to these two working hypotheses, the isomeric conformation changes of amyloid-beta, tau, alpha-synuclein, huntingtin, TDP-43 and prion protein, and their assembly into various protein complexes, including oligomers, plaques and tangles, are protein misfolding or prion replication events.
By defining the isomeric conformational changes and assembly of these proteins into oligomers and larger protein complexes as protein misfolding or prion replication activities, the protein misfolding concept and the prion hypothesis set up a strong conceptual barrier in connecting the pathogenic mechanisms leading to neurodegeneration with the physiological function of these proteins. Indeed, very few, if any, of the thousands of studies (including the study by Heneka et al.) that addressed the isomeric conformational changes and assembly of these proteins, or the pathogenic mechanisms causing neurodegeneration, have considered the physiological function of these proteins as a key factor in the disease; and, this makes perfect sense considering that by definition these processes are misfolding or prion replication events.
Recently, I proposed a radical new model on the physiological functions of these proteins and on the pathogenic mechanisms and etiology of AD, PD, ALS, HD, CJD and other neurodegenerative diseases (3, 4). According to this model which is consistent with the current experimental data and observations and explains and integrates many of the enigmatic data and observations in these fields:
(i) A-beta/APP, tau, ?-synuclein, huntingtin, TDP-43, prion protein, and other primary proteins implicated in neurodegenerative diseases are members or components of the innate immune system;
(ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire of activities;
(iii) The immune reactions and activities associated with the function of these proteins in innate immunity lead to AD, PD, ALS, HD, CJD and other neurodegenerative diseases, which are innate immunity disorders.
In context of this radical new theory, the findings reported by Heneka et al. as well hundreds of other significant but disparate findings on AD and other neurodegenerative diseases make biological and evolutionary sense. This theory could generate a wealth of new information and knowledge be serving as a model for reinterpreting the vast amounts of existing experimental data and observations, a process that fortunately would require little if any funding. Moreover, this model provides new ways of thinking about prevention and therapy, which should be of urgent interest considering the enormous medical, social and economic burden associated with this group of diseases. Additionally, this model might have implications on the understanding of some of the most fundamental aspects in biochemistry and biology, such as protein folding.
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Peter Gibson
Further to Heneka et al Letter and Bandea?s comments: I have looked at hundreds of 10 mm slices of formalin preserved autopsy Alzheimer?s brains and they showed no visible signs of inflammation. They were sampled from a variety of areas including several neocortical areas and looked at with a variety of histological stains. The brains came from a spectrum of people with varying degrees of psychometrically assessed dementia. A subset of these areas was examined at by electron microscopy. The lesions seen were normal for the disease: neuritic and amyloid plaques in particular. The astrocytes and microglia had apparently increased in number but the capillaries looked normal. There were lysosomes and much unidentifiable fragments of membranes. There was always some vacuolation but most of this will have been due to post-mortem change. This picture has been well described by others as Bandea notes. The two things that always struck me were that at the EM level although microglia were possibly more numerous there was never any indication of phagocytosis. The most characteristic profile was of strands of putative amyloid and large areas destruction. Again this has been all described by numerous people.
The findings of Heneka et al suggest that they are looking at a reaction to pre-existing structural damage accumulated over a long period. People have for decades been pinning this damage of amyloid or whatever ones wishes to call it. In spite of what Bandea says I do not see the Heneda et al takes us any further forward. It is a technical up-date of what has been known for a long time.