The TRPV1-PKM2-SREBP1 Axis Maintains Microglial Lipid Homeostasis in Alzheimer's Disease

Overview

Journal Cell Death Dis

Date 2025 Jan 14

PMID 39809738

Authors

Xudong Sha

Jiayuan Lin

Kexin Wu

Jia Lu

Zhihua Yu

Affiliations

Soon will be listed here.

Abstract

Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.

References

Zhang Q, Luo P, Xia F, Tang H, Chen J, Zhang J . Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell Chem Biol. 2022; 29(8):1248-1259.e6. DOI: 10.1016/j.chembiol.2022.06.011. View

Peng C, Yang P, Zhang D, Jin C, Peng W, Wang T . KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2. Acta Pharm Sin B. 2024; 14(7):2959-2976. PMC: 11252482. DOI: 10.1016/j.apsb.2024.04.024. View

Zhong W, Rao Z, Xu J, Sun Y, Hu H, Wang P . Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell. 2022; 21(6):e13622. PMC: 9197407. DOI: 10.1111/acel.13622. View

Akhtar K, Gupta V, Koul A, Alam N, Bhat R, Bamezai R . Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme. J Biol Chem. 2009; 284(18):11971-81. PMC: 2673266. DOI: 10.1074/jbc.M808761200. View

Horton J, Goldstein J, Brown M . SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002; 109(9):1125-31. PMC: 150968. DOI: 10.1172/JCI15593. View

Liu F, Ma M, Gao A, Ma F, Ma G, Liu P . PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability. EMBO J. 2021; 40(22):e108065. PMC: 8591543. DOI: 10.15252/embj.2021108065. View

Angiari S, Runtsch M, Sutton C, Palsson-McDermott E, Kelly B, Rana N . Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4 T Cell Pathogenicity and Suppresses Autoimmunity. Cell Metab. 2019; 31(2):391-405.e8. PMC: 7001035. DOI: 10.1016/j.cmet.2019.10.015. View

Zhao B, Wang Y, Liu R, Jia X, Hu N, An X . Rutaecarpine Ameliorated High Sucrose-Induced Alzheimer's Disease Like Pathological and Cognitive Impairments in Mice. Rejuvenation Res. 2020; 24(3):181-190. DOI: 10.1089/rej.2020.2349. View

Willemsen J, Neuhoff M, Hoyler T, Noir E, Tessier C, Sarret S . TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis. Cell Rep. 2021; 37(6):109977. DOI: 10.1016/j.celrep.2021.109977. View

10.

Lu J, Zhou W, Dou F, Wang C, Yu Z . TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease. EMBO Rep. 2021; 22(6):e52013. PMC: 8183394. DOI: 10.15252/embr.202052013. View

11.

Johnson E, Dammer E, Duong D, Ping L, Zhou M, Yin L . Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020; 26(5):769-780. PMC: 7405761. DOI: 10.1038/s41591-020-0815-6. View

12.

Wang C, Lu J, Sha X, Qiu Y, Chen H, Yu Z . TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia. Exp Mol Med. 2023; 55(2):347-363. PMC: 9981624. DOI: 10.1038/s12276-023-00935-z. View

13.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

14.

McArthur K, Whitehead L, Heddleston J, Li L, Padman B, Oorschot V . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018; 359(6378). DOI: 10.1126/science.aao6047. View

15.

Johnson E, Carter E, Dammer E, Duong D, Gerasimov E, Liu Y . Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level. Nat Neurosci. 2022; 25(2):213-225. PMC: 8825285. DOI: 10.1038/s41593-021-00999-y. View

16.

Mi Y, Qi G, Vitali F, Shang Y, Raikes A, Wang T . Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration. Nat Metab. 2023; 5(3):445-465. PMC: 10202034. DOI: 10.1038/s42255-023-00756-4. View

17.

Zhao X, Zhao L, Yang H, Li J, Min X, Yang F . Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma. J Biol Chem. 2018; 293(17):6623-6634. PMC: 5925817. DOI: 10.1074/jbc.RA117.000100. View

18.

Christofk H, Vander Heiden M, Wu N, Asara J, Cantley L . Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008; 452(7184):181-6. DOI: 10.1038/nature06667. View

19.

Wei T, Wang Y, Xu W, Liu Y, Chen H, Yu Z . KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3β pathway. Neurobiol Dis. 2019; 132:104588. DOI: 10.1016/j.nbd.2019.104588. View

20.

Vorhees C, Williams M . Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2007; 1(2):848-58. PMC: 2895266. DOI: 10.1038/nprot.2006.116. View