Toll-Like Receptor 4 Plays a Significant Role in the Biochemical and Neurological Alterations Observed in Two Distinct Mice Models of Huntington’s Disease

• Published in: Molecular neurobiology Vol. 60; no. 5; pp. 2678 - 2690
• Main Authors: Martínez-Gopar, Pablo E., Pérez-Rodríguez, Marian J., Angeles-López, Quetzalli D., Tristán-López, Luis, González-Espinosa, Claudia, Pérez-Severiano, Francisca
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-05-2023; Springer Nature B.V
• Subjects: Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Coding; Corpus Striatum - metabolism; Disease; Disease Models, Animal; Glial cells; Huntingtin; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington's disease; Huntingtons disease; Inflammation; Innate immunity; Laboratory animals; Mice; Mice, Transgenic; Motor ability; Motor activity; Mutation; Neostriatum; Neurobiology; Neurodegeneration; Neurology; Neuronal-glial interactions; Neurons - metabolism; Neurosciences; Phenotypes; Proteins; Quinolinic acid; Therapeutic targets; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; γ-Aminobutyric acid; Behavioral changes; Huntington’s disease; Quinolinic acid; R6/1 mice; Oxidative damage; Toll-like receptor 4
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03234-w

Toll-like receptors (TLRs) are central players in innate immunity responses. They are expressed in glial cells and neurons, and their overactivation leads to the production of proinflammatory molecules, neuroinflammation, and neural damage associated with many neurodegenerative pathologies, such as Huntington’s disease (HD). HD is an inherited disorder caused by a mutation in the gene coding for the protein Huntingtin (Htt). Expression of mutated Htt (mHtt) causes progressive neuronal degeneration characterized by striatal loss of GABAergic neurons, oxidative damage, neuroinflammatory processes, and impaired motor behavior. The main animal models to study HD are the intrastriatal injection of quinolinic acid (QA) and the transgenic B6CBA-Tg (HDexon1)61Gpb/1 J mice (R6/1). Those models mimic neuronal damage and systemic manifestations of HD. The objective of this work was to study the participation of TLR4 in the manifestations of neuronal damage and HD symptoms in the two mentioned models. For this purpose, C57BL6/J and TLR4-KO mice were administered with QA, and after that motor activity, and neuronal and oxidative damages were measured. R6/1 and TLR4-KO were mated to study the effect of low expression of TLR4 on the phenotype manifestation in R6/1 mice. We found that TLR4 is involved in motor activity, and neurological and oxidative damage induced by intrastriatal injection of QA, and the low expression of TLR4 causes a delay in the onset of phenotypic manifestations by the mHtt expression in R6/1 mice. Our results show that TLR4 is involved in both models of HD and focuses then as a therapeutic target for some deleterious reactions in HD.