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The Role of Neuronal NLRP1 Inflammasome in Alzheimer’s Disease: Bringing Neurons into the Neuroinflammation Game

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Abstract

The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer’s disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates, and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β (IL-1β) and interleukin-18 (IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the Nlrp1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.

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Acknowledgments

Funding for this work was from the Fundamental Research Grant Scheme (FRGS/1/2016/SKK08/IMU/03/1) by the Ministry of Higher Education of Malaysia.

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Authors and Affiliations

  1. School of Postgraduate Studies, International Medical University, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Jeremy Kean Yi Yap

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Hamnett Wing, 161, Cathedral Street, Glasgow, G4 0RE, UK

    Benjamin Simon Pickard

  3. Institute for Research, Development and Innovation, International Medical University, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Elaine Wan Ling Chan

  4. Department of Life Sciences, School of Pharmacy, International Medical University, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Sook Yee Gan

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  1. Jeremy Kean Yi Yap
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Correspondence to Sook Yee Gan.

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Yap, J.K.Y., Pickard, B.S., Chan, E.W.L. et al. The Role of Neuronal NLRP1 Inflammasome in Alzheimer’s Disease: Bringing Neurons into the Neuroinflammation Game. Mol Neurobiol 56, 7741–7753 (2019). https://doi.org/10.1007/s12035-019-1638-7

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