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Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.

ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells (CD4+ and CD8+ T cells) and the frequency of effector memory phenotype CD4+ T cells were decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD.

SUBMITTER: Lee SW

PROVIDER: S-EPMC6138304 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.

Lee Sung Won SW Park Hyun Jung HJ Im Wooseok W Kim Manho M Hong Seokmann S

Animal cells and systems 20180620 4

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 an ...[more]

PMID: 30460101

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Project description:Huntington's disease (HD) is a fatal genetic neurological disorder caused by a mutation in the human Huntingtin (HTT) gene. This mutation confers a toxic gain of function of the encoded mutant huntingtin (mHTT) protein, leading to widespread neuropathology including the formation of mHTT-positive inclusion bodies, gene dysregulation, reduced levels of adult dentate gyrus neurogenesis and neuron loss throughout many regions of the brain. Additionally, because HTT is ubiquitously expressed, several peripheral tissues are also affected. HD patients suffer from progressive motor, cognitive, psychiatric, and metabolic symptoms, including weight loss and skeletal muscle wasting. HD patients also show neuroendocrine changes including a robust, significant elevation in circulating levels of the glucocorticoid, cortisol. Previously, we confirmed that the R6/2 mouse model of HD exhibits elevated corticosterone (the rodent homolog of cortisol) levels and demonstrated that experimentally elevated corticosterone exacerbates R6/2 HD symptomology, resulting in severe and rapid weight loss and a shorter latency to death. Given that efficacious therapeutics are lacking for HD, here we investigated whether normalizing glucocorticoid levels could serve as a viable therapeutic approach for this disease. We tested the hypothesis that normalizing glucocorticoids to wild-type levels would ameliorate HD symptomology. Wild-type (WT) and transgenic R6/2 mice were allocated to three treatment groups: 1) adrenalectomy with normalized, WT-level corticosterone replacement (10??g/ml), 2) adrenalectomy with high HD-level corticosterone replacement (35??g/ml), or 3) sham surgery with no corticosterone replacement. Normalizing corticosterone to WT levels led to an improvement in metabolic rate in male R6/2 mice, as indicated by indirect calorimetry, including a reduction in oxygen consumption and normalization of respiratory exchange ratio values (p?<?.05 for both). Normalizing corticosterone also ameliorated brain atrophy in female R6/2 mice and skeletal muscle wasting in both male and female R6/2 mice (p?<?.05 for all). Female R6/2 mice given WT-level corticosterone replacement also showed a reduction in HD neuropathological markers, including a reduction in mHTT inclusion burden in the striatum, cortex, and hippocampus (p?<?.05 for all). This data illustrates that ameliorating glucocorticoid dysregulation leads to a significant improvement in HD symptomology in the R6/2 mouse model and suggests that cortisol-reducing therapeutics may be of value in improving HD patient quality of life.

Dataset Information

Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.

Publications

Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.

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