Neuroinflammation in Huntington's Disease: A Starring Role for Astrocyte and Microglia

Overview

Journal Curr Neuropharmacol

Publisher Bentham Science Publishers

Date 2021 Dec 2

PMID 34852742

Citations 33

Authors

Julieta Saba

Federico Lopez Couselo

Julieta Bruno

Lila Carniglia

Daniela Durand

Mercedes Lasaga

Carla Caruso

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.

Citing Articles

Neurodegenerative diseases and neuroinflammation-induced apoptosis.

Huang S, Lu Y, Fang W, Huang Y, Li Q, Xu Z Open Life Sci. 2025; 20(1):20221051.

PMID: 40026360 PMC: 11868719. DOI: 10.1515/biol-2022-1051.

Neuroinflammation and neurodegeneration in Huntington's disease: genetic hallmarks, role of metals and organophosphates.

Kunwar O, Singh S Neurogenetics. 2025; 26(1):21.

PMID: 39820855 DOI: 10.1007/s10048-025-00801-2.

Unraveling the transcriptomic landscape of brain vascular cells in dementia: A systematic review.

Sewell M, Fialova N, Montagne A Alzheimers Dement. 2025; 21(2):e14512.

PMID: 39807599 PMC: 11851133. DOI: 10.1002/alz.14512.

Circadian Influences on Brain Lipid Metabolism and Neurodegenerative Diseases.

Hussain Y, Dar M, Pan X Metabolites. 2024; 14(12).

PMID: 39728504 PMC: 11677446. DOI: 10.3390/metabo14120723.

Mitigating neurodegenerative diseases: the protective influence of baicalin and baicalein through neuroinflammation regulation.

Yang R, Wang R, Xu A, Zhang J, Ma J Front Pharmacol. 2024; 15:1425731.

PMID: 39687298 PMC: 11647303. DOI: 10.3389/fphar.2024.1425731.

References

Weiss A, Trager U, Wild E, Grueninger S, Farmer R, Landles C . Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression. J Clin Invest. 2012; 122(10):3731-6. PMC: 3461928. DOI: 10.1172/JCI64565. View

Jang M, Choi J, Chang Y, Lee S, Nah S, Cho I . Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain Behav Immun. 2019; 80:146-162. DOI: 10.1016/j.bbi.2019.03.001. View

Laprairie R, Warford J, Hutchings S, Robertson G, Kelly M, Denovan-Wright E . The cytokine and endocannabinoid systems are co-regulated by NF-κB p65/RelA in cell culture and transgenic mouse models of Huntington's disease and in striatal tissue from Huntington's disease patients. J Neuroimmunol. 2013; 267(1-2):61-72. DOI: 10.1016/j.jneuroim.2013.12.008. View

Benraiss A, Mariani J, Osipovitch M, Cornwell A, Windrem M, Villanueva C . Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease. Cell Rep. 2021; 36(1):109308. DOI: 10.1016/j.celrep.2021.109308. View

Ehrnhoefer D, Southwell A, Sivasubramanian M, Qiu X, Villanueva E, Xie Y . HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo. Hum Mol Genet. 2017; 27(2):239-253. PMC: 5886116. DOI: 10.1093/hmg/ddx394. View

Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D, Mauceri J . Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun. 2016; 7:11758. PMC: 4899632. DOI: 10.1038/ncomms11758. View

Yu X, Nagai J, Marti-Solano M, Soto J, Coppola G, Babu M . Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable. Neuron. 2020; 108(6):1146-1162.e10. PMC: 7813554. DOI: 10.1016/j.neuron.2020.09.021. View

Mantovani S, Gordon R, Li R, Christie D, Kumar V, Woodruff T . Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice. Hum Mol Genet. 2016; 25(9):1780-91. DOI: 10.1093/hmg/ddw050. View

Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G . In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum Mol Genet. 2010; 19(15):3053-67. PMC: 2901144. DOI: 10.1093/hmg/ddq212. View

10.

Kierdorf K, Prinz M . Microglia in steady state. J Clin Invest. 2017; 127(9):3201-3209. PMC: 5669563. DOI: 10.1172/JCI90602. View

11.

Bouchard J, Truong J, Bouchard K, Dunkelberger D, Desrayaud S, Moussaoui S . Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington's disease. J Neurosci. 2012; 32(50):18259-68. PMC: 3753072. DOI: 10.1523/JNEUROSCI.4008-12.2012. View

12.

Schilling G, Becher M, Sharp A, Jinnah H, Duan K, Kotzuk J . Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999; 8(3):397-407. DOI: 10.1093/hmg/8.3.397. View

13.

Tabrizi S, Flower M, Ross C, Wild E . Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol. 2020; 16(10):529-546. DOI: 10.1038/s41582-020-0389-4. View

14.

Lee W, Reyes R, Gottipati M, Lewis K, Lesort M, Parpura V . Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model. Neurobiol Dis. 2013; 58:192-9. PMC: 3748209. DOI: 10.1016/j.nbd.2013.06.002. View

15.

Mehrabi N, Waldvogel H, Tippett L, Hogg V, Synek B, Faull R . Symptom heterogeneity in Huntington's disease correlates with neuronal degeneration in the cerebral cortex. Neurobiol Dis. 2016; 96:67-74. DOI: 10.1016/j.nbd.2016.08.015. View

16.

Chafekar S, Duennwald M . Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One. 2012; 7(5):e37929. PMC: 3359295. DOI: 10.1371/journal.pone.0037929. View

17.

El-Abhar H, Abd El Fattah M, Wadie W, El-Tanbouly D . Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington's disease. PLoS One. 2018; 13(9):e0203837. PMC: 6160003. DOI: 10.1371/journal.pone.0203837. View

18.

Pido-Lopez J, Tanudjojo B, Farag S, Bondulich M, Andre R, Tabrizi S . Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington's disease by etanercept treatment. Sci Rep. 2019; 9(1):7202. PMC: 6510744. DOI: 10.1038/s41598-019-43627-3. View

19.

Verkhratsky A, Nedergaard M . Physiology of Astroglia. Physiol Rev. 2018; 98(1):239-389. PMC: 6050349. DOI: 10.1152/physrev.00042.2016. View

20.

Faraco G, Fossati S, Bianchi M, Patrone M, Pedrazzi M, Sparatore B . High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem. 2007; 103(2):590-603. DOI: 10.1111/j.1471-4159.2007.04788.x. View