Spatial Regulation of NMN Supplementation on Brain Lipid Metabolism Upon Subacute and Sub-chronic PM Exposure in C57BL/6 Mice

Overview

Journal Part Fibre Toxicol

Publisher Biomed Central

Specialty Toxicology

Date 2024 Sep 9

PMID 39252011

Authors

Yue Jiang

Fang Li

Lizhu Ye

Rui Zhang

Shen Chen

Hui Peng

Haiyan Zhang

Daochuan Li

Liping Chen

Xiaowen Zeng

Guanghui Dong

Wei Xu

Chunyang Liao

Rong Zhang

Qian Luo

Wen Chen

Affiliations

Soon will be listed here.

Abstract

Background: Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed.

Results: In this study, we examine the effect of β-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis.

Conclusions: This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.

References

Hajipour S, Farbood Y, Gharib-Naseri M, Goudarzi G, Rashno M, Maleki H . Exposure to ambient dusty particulate matter impairs spatial memory and hippocampal LTP by increasing brain inflammation and oxidative stress in rats. Life Sci. 2019; 242:117210. DOI: 10.1016/j.lfs.2019.117210. View

Turner J, Licollari A, Mihalcea E, Tan A . Safety Evaluation for Restorin® NMN, a NAD+ Precursor. Front Pharmacol. 2021; 12:749727. PMC: 8632654. DOI: 10.3389/fphar.2021.749727. View

Wu S, Wu B, Liu M, Chen Z, Wang W, Anderson C . Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol. 2019; 18(4):394-405. DOI: 10.1016/S1474-4422(18)30500-3. View

Eurtivong C, Leung E, Sharma N, Leung I, Reynisson J . Phosphatidylcholine-Specific Phospholipase C as a Promising Drug Target. Molecules. 2023; 28(15). PMC: 10420013. DOI: 10.3390/molecules28155637. View

Sumida H, Lu E, Chen H, Yang Q, Mackie K, Cyster J . GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage. Sci Immunol. 2017; 2(18). PMC: 5847323. DOI: 10.1126/sciimmunol.aao1135. View

Campbell J . Supplementation with NAD and Its Precursors to Prevent Cognitive Decline across Disease Contexts. Nutrients. 2022; 14(15). PMC: 9370773. DOI: 10.3390/nu14153231. View

Younan D, Petkus A, Widaman K, Wang X, Casanova R, Espeland M . Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease. Brain. 2019; 143(1):289-302. PMC: 6938036. DOI: 10.1093/brain/awz348. View

Hikosaka K, Yaku K, Okabe K, Nakagawa T . Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutr Neurosci. 2019; 24(5):371-383. DOI: 10.1080/1028415X.2019.1637504. View

Klimova N, Fearnow A, Long A, Kristian T . NAD precursor modulates post-ischemic mitochondrial fragmentation and reactive oxygen species generation via SIRT3 dependent mechanisms. Exp Neurol. 2019; 325:113144. PMC: 8328278. DOI: 10.1016/j.expneurol.2019.113144. View

10.

Petkus A, Younan D, Widaman K, Gatz M, Manson J, Wang X . Exposure to fine particulate matter and temporal dynamics of episodic memory and depressive symptoms in older women. Environ Int. 2019; 135:105196. PMC: 7499893. DOI: 10.1016/j.envint.2019.105196. View

11.

Weerasinghe-Mudiyanselage P, Ang M, Kang S, Kim J, Moon C . Structural Plasticity of the Hippocampus in Neurodegenerative Diseases. Int J Mol Sci. 2022; 23(6). PMC: 8955928. DOI: 10.3390/ijms23063349. View

12.

Pant D, Aguilera-Albesa S, Pujol A . Ceramide signalling in inherited and multifactorial brain metabolic diseases. Neurobiol Dis. 2020; 143:105014. DOI: 10.1016/j.nbd.2020.105014. View

13.

Zhang R, Chen S, Wang Z, Ye L, Jiang Y, Li M . Assessing the Effects of Nicotinamide Mononucleotide Supplementation on Pulmonary Inflammation in Male Mice Subchronically Exposed to Ambient Particulate Matter. Environ Health Perspect. 2023; 131(7):77006. PMC: 10351503. DOI: 10.1289/EHP12259. View

14.

Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T . Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Front Nutr. 2022; 9:868640. PMC: 9036060. DOI: 10.3389/fnut.2022.868640. View

15.

Stebounova L, Adamcakova-Dodd A, Kim J, Park H, OShaughnessy P, Grassian V . Nanosilver induces minimal lung toxicity or inflammation in a subacute murine inhalation model. Part Fibre Toxicol. 2011; 8(1):5. PMC: 3040688. DOI: 10.1186/1743-8977-8-5. View

16.

Yung Y, Stoddard N, Mirendil H, Chun J . Lysophosphatidic Acid signaling in the nervous system. Neuron. 2015; 85(4):669-82. PMC: 4400838. DOI: 10.1016/j.neuron.2015.01.009. View

17.

Calderon-Garciduenas L, Gonzalez-Maciel A, Reynoso-Robles R, Hammond J, Kulesza R, Lachmann I . Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key.... Environ Res. 2020; 191:110139. DOI: 10.1016/j.envres.2020.110139. View

18.

Choi J, Chun J . Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta. 2012; 1831(1):20-32. PMC: 3693945. DOI: 10.1016/j.bbalip.2012.07.015. View

19.

Churilova A, Zachepilo T, Baranova K, Rybnikova E . Differences in the Autophagy Response to Hypoxia in the Hippocampus and Neocortex of Rats. Int J Mol Sci. 2022; 23(14). PMC: 9320385. DOI: 10.3390/ijms23148002. View

20.

Xu Y, Hong H, Lin X, Tong T, Zhang J, He H . Chronic cadmium exposure induces Parkinson-like syndrome by eliciting sphingolipid disturbance and neuroinflammation in the midbrain of C57BL/6J mice. Environ Pollut. 2023; 337:122606. DOI: 10.1016/j.envpol.2023.122606. View