GPCR19 Regulates P2X7R-Mediated NLRP3 Inflammasomal Activation of Microglia by Amyloid β in a Mouse Model of Alzheimer's Disease

Jahirul Islam; Jung-Ah Cho; Ju-Yong Kim; Kyung-Sun Park; Young-Jae Koh; Chu Young Chung; Eun-Jae Lee; Soo Jeong Nam; Kyoungyul Lee; Seoung-Heon Kim; Sung-Hye Park; Dong Young Lee; Byeong C Kim; Kyung-Hwa Lee; Seung-Yong Seong

doi:10.3389/fimmu.2022.766919

GPCR19 Regulates P2X7R-Mediated NLRP3 Inflammasomal Activation of Microglia by Amyloid β in a Mouse Model of Alzheimer's Disease

Front Immunol. 2022 Apr 6:13:766919. doi: 10.3389/fimmu.2022.766919. eCollection 2022.

Authors

Jahirul Islam^{1

2}, Jung-Ah Cho¹, Ju-Yong Kim¹, Kyung-Sun Park¹, Young-Jae Koh³, Chu Young Chung³, Eun-Jae Lee⁴, Soo Jeong Nam⁵, Kyoungyul Lee⁶, Seoung-Heon Kim⁷, Sung-Hye Park⁸, Dong Young Lee⁹, Byeong C Kim¹⁰, Kyung-Hwa Lee¹¹, Seung-Yong Seong^{1

2

3

12}

Affiliations

¹ Wide River Institute of Immunology, Seoul National University College of Medicine, Seoul, South Korea.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
³ Department of Inflammation, Shaperon Inc. Ltd, Seoul, South Korea.
⁴ Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.
⁵ Department of Pathology, Asan Medical Center, Seoul, South Korea.
⁶ Department of Pathology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, South Korea.
⁷ Department of Neurology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, South Korea.
⁸ Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
⁹ Department of Neuropsychiatry, Seoul National University College of Medicine, Seoul, South Korea.
¹⁰ Department of Neurology, Chonnam National University Medical School, Gwangju, South Korea.
¹¹ Department of Pathology, Chonnam National University Hwasun Hospital and Medical School, Gwangju, South Korea.
¹² Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.

Abstract

Amyloid β (Aβ) and/or ATP activate the NLRP3 inflammasome (N3I) via P2X7R in microglia, which is crucial in neuroinflammation in Alzheimer's disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2X7R, inhibition of P2X7R has not been effective for AD. We first report that taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2X7R expression and P2X7R-mediated Ca⁺⁺ mobilization and N3I oligomerization, which is essential for production of IL-1β/IL-18 by microglia. Furthermore, TDCA enhanced phagocytosis of Aβ and decreased the number of Aβ plaques in the brains of 5x Familial Alzheimer's disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function in 5xFAD mice. The pleiotropic roles of GPCR19 in P2X7R-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

Keywords: Alzheimer’s disease; GPCR19; P2X7R; inflammasome; neuroinflammation; taurodeoxycholate.

MeSH terms

Alzheimer Disease* / metabolism
Amyloid beta-Peptides* / metabolism
Animals
Disease Models, Animal
Humans
Inflammasomes / metabolism
Mice
Microglia / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism

Substances

Amyloid beta-Peptides
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse