NLRP1 inflammasome in neurodegenerative disorders: From pathology to therapies

Meng-Jie Zhang; Long Yang; Zhuo-Yao Li; Long-Yun Zhou; Yong-Jun Wang; Hong-Shen Wang; Xue-Jun Cui; Min Yao

doi:10.1016/j.cytogfr.2024.10.004

NLRP1 inflammasome in neurodegenerative disorders: From pathology to therapies

Cytokine Growth Factor Rev. 2024 Oct 16:S1359-6101(24)00083-2. doi: 10.1016/j.cytogfr.2024.10.004. Online ahead of print.

Authors

Meng-Jie Zhang¹, Long Yang², Zhuo-Yao Li¹, Long-Yun Zhou³, Yong-Jun Wang⁴, Hong-Shen Wang⁵, Xue-Jun Cui⁶, Min Yao⁷

Affiliations

¹ Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
² Rehabilitation Medicine Department, Shanghai Eighth People's Hospital, Shanghai 200235, China.
³ Rehabilitation Medicine Center, Jiangsu Provincial People's Hospital, Jiangsu 210029, China.
⁴ Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: nyfczh@163.com.
⁵ Orthopedics Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
⁶ Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: 13917715524@139.com.
⁷ Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: yaomin19871223@126.com.

PMID: 39443194
DOI: 10.1016/j.cytogfr.2024.10.004

Abstract

Neuroinflammation is a critical component in neurodegenerative disorders. The inflammasome, facilitates the cleavage of caspase-1, leading to the maturation and subsequent secretion of inflammatory factors interleukin (IL)-1β and IL-18. Consequently, pyroptosis mediated by gasdermin D, exacerbates neuroinflammation. Among the inflammasomes, NLRP1/3 are predominant in the central nervous system (CNS), Although NLRP1 was the earliest discovered inflammasome, the specific involvement of NLRP1 in neurodegenerative diseases remains to be fully elucidated. Recently, the discovery of an endogenous inhibitor of NLRP1, dipeptidyl peptidase 9, suggests the feasibility of producing of small-molecule drugs targeting NLRP1. This review describes the latest findings on the role of the NLRP1 inflammasome in the pathology of neurodegenerative disorders, including Alzheimer's disease, and summarises the regulatory mechanisms of NLRP1 inflammasome activation in the CNS. Furthermore, we highlight the recent progress in developing small-molecule and biological inhibitors that modulate the NLRP1 infammasome for the treatment of neurodegenerative disorders, some of which are advancing to preclinical testing. SIGNIFICANCE STATEMENT: The objective of this review is to synthesise the research on the structure, activation, and regulatory mechanisms of the NLRP1 inflammasome, along with its potential impact on both acute and chronic neurodegenerative conditions. The discovery of endogenous inhibitors, such as dipeptidyl peptidase 9 and thioredoxin, and their interaction with NLRP1 suggest the possibility of developing NLRP1-targeted small-molecule drugs for the treatment of neurodegenerative disorders. This review also discusses the use of both direct and indirect NLRP1 inhibitors as prospective therapeutic strategies for these conditions.

Keywords: Blood-brain barrier; Inflammasome inhibitors; NLRP1 inflammasomes; Neurodegenerative disorders; Neuroinflammation.

Publication types

Review