scholarly journals A novel Huntington's disease mouse model to assess the role of neuroinflammation on disease progression and to develop human cell therapies

2021 ◽  
Author(s):  
Heather Dahlenburg ◽  
David Cameron ◽  
Sheng Yang ◽  
Angelica Bachman ◽  
Kari Pollock ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Human Cell ◽  
Cell Therapies

scholarly journals Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

2018 ◽  
Vol 33 (5) ◽  
pp. 535-554 ◽  
Author(s):  
Daniel S. Whittaker ◽  
Dawn H. Loh ◽  
Huei-Bin Wang ◽  
Yu Tahara ◽  
Dika Kuljis ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Sleep Onset ◽  
Lifestyle Changes ◽  
Disease Stage ◽  
Preclinical Model ◽  
Delay Disease Progression ◽  
Circadian Dysfunction

Huntington’s disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

Intraventricular Administration of a Caspase Inhibitor Delays Disease Progression and Mortality in a Mouse Model of Huntington's Disease

Neurosurgery ◽  
1999 ◽  
Vol 45 (3) ◽  
pp. 718-718 ◽  
Author(s):  
Robert Friedlander ◽  
Victor O. Ona ◽  
Mingwei Li ◽  
Jean Paul G. Vonsattel ◽  
L. John Andrews ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Intraventricular Administration ◽  
Caspase Inhibitor

scholarly journals The Role of the Immune System in Huntington’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Gisa Ellrichmann ◽  
Christiane Reick ◽  
Carsten Saft ◽  
Ralf A. Linker
Keyword(s):  
Immune System ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Adaptive Immune System ◽  
Cag Repeats ◽  
Adaptive Immune ◽  
Adaptive Immune Systems ◽  
Migration Of Macrophages

Huntington’s disease (HD) is characterized by a progressive course of disease until death 15–20 years after the first symptoms occur and is caused by a mutation with expanded CAG repeats in the huntingtin (htt) protein. Mutant htt (mhtt) in the striatum is assumed to be the main reason for neurodegeneration. Knowledge about pathophysiology has rapidly improved discussing influences of excitotoxicity, mitochondrial damage, free radicals, and inflammatory mechanisms. Both innate and adaptive immune systems may play an important role in HD. Activation of microglia with expression of proinflammatory cytokines, impaired migration of macrophages, and deposition of complement factors in the striatum indicate an activation of the innate immune system. As part of the adaptive immune system, dendritic cells (DCs) prime T-cell responses secreting inflammatory mediators. In HD, DCs may contain mhtt which brings the adaptive immune system into the focus of interest. These data underline an increasing interest in the peripheral immune system for pathomechanisms of HD. It is still unclear if neuroinflammation is a reactive process or if there is an active influence on disease progression. Further understanding the influence of inflammation in HD using mouse models may open various avenues for promising therapeutic approaches aiming at slowing disease progression or forestalling onset of disease.

scholarly journals Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Marley Realing ◽  
Jason P. Gigley ◽  
Jonathan H. Fox
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Microglial Activation ◽  
Iron Supplementation ◽  
Kynurenine Pathway ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Degradation ◽  
Microglial Morphology

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine-2,3-dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron-supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171-82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD.

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