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박미의Miey Park

가천대학교

Redox Biol., May 16 2024, 73 S2213-2317(24)00175-7 | https://doi.org/10.1016/j.redox.2024.103197 Nobiletin regulates intracellular Ca2+ levels via IP3R and ameliorates neuroinflammation in Aβ42-induced astrocytes

Sanjay^a, Rachit Sood ^a,b, Varun Jaiswal ^a,b, Sung-Ung Kang ^c,d, Miey Park ^a,b, Hae-Jeung Lee^a,b,e

^aInstitute for Aging and Clinical Nutrition Research, Gachon University, Seongnam, Gyeonggi-do, 13120, Republic of Korea

^bDepartment of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi-do, 13120, Republic of Korea

^cNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

^dDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

^eDepartment of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea

Corresponding authors : Miey Park, Hae-Jeung Lee

Abstract

Astrocytes are the major glial cells in the human brain and provide crucial metabolic and trophic support to neurons. The amyloid-β peptide (Aβ) alter the morphological and functional properties of astrocytes and induce inflammation and calcium dysregulation, contributing to Alzheimer's disease (AD) pathology. Recent studies highlight the role of Toll-like receptor (TLR) 4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in inflammation. Reactive oxygen species (ROS) generated due to Aβ, induce apoptosis in the brain cells worsening AD progression. Astrocytic cell surface receptors, such as purinergic receptors (P2Y1 and P2Y2), metabotropic glutamate receptor (mGLUR)5, α7 nicotinic acetylcholine receptor (α7nAChR), and N-methyl-d-aspartate receptors (NMDARs), have been suggested to interact with inositol trisphosphate receptor (IP ₃R) on the endoplasmic reticulum (ER) to induce Ca ²⁺ movement from ER to cytoplasm, causing Ca ²⁺ dysregulation. We found that the citrus flavonoid nobiletin (NOB) protected primary astrocytes from Aβ42-induced cytotoxicity and inhibited TLR4/NF-κB signaling in Aβ42-induced primary rat astrocytes. NOB was found to regulate Aβ42-induced ROS levels through Keap1-Nrf2 pathway. The receptors P2Y1, P2Y2, mGLUR5, α7nAChR, and NMDARs induced intracellular Ca ²⁺ levels by activating IP ₃R and NOB regulated them, thereby regulating intracellular Ca ²⁺ levels. Molecular docking analysis revealed a possible interaction between NOB and IP ₃R in IP ₃R regulation. Furthermore, RNA sequencing revealed various NOB-mediated biological signaling pathways, such as the AD-presenilin, AD-amyloid secretase, and Wnt signaling pathway, suggesting possible neuroprotective roles of NOB. To conclude, NOB is a promising therapeutic agent for AD and works by modulating AD pathology at various levels in Aβ42-induced primary rat astrocytes.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-27)
연구진국내(교신)+국외 연구진
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