Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers

Politis, Marios; Lahiri, Nayanjot; Niccolini, Flavia; Su, Paul; Wu, Kit; Giannetti, Paolo; Scahill, Rachael I.; Turkheimer, Federico; Tabrizi, Sarah J.; Piccini, Paola

doi:10.1016/j.nbd.2015.08.011

Cited by 138 publications

(97 citation statements)

References 51 publications

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“…More recently, increased microglial activation in somatosensory cortex (as evaluated through 11 C-PK11195 binding) was associated with higher plasma levels of IL-1 β , IL-6, IL-8, and TNF- α in premanifest HD gene carriers [26]. …”

Section: Central Nervous System Inflammationmentioning

confidence: 99%

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

Rocha

Ribeiro

Furr-Stimming

et al. 2016

Mediators of Inflammation

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Huntington's disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described—HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3—the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.

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Section: Central Nervous System Inflammationmentioning

confidence: 99%

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

Rocha

Ribeiro

Furr-Stimming

et al. 2016

Mediators of Inflammation

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“…Human HD monocytes demonstrate hyper-responsive pro-inflammatory cytokine production in response to lipopolysaccharide which stimulates innate immune response [9]. Further, studies in human HD have demonstrated pre-clinical elevations of serum pro-inflammatory cytokines [4, 10]. Studies in genetic mouse models of HD largely recapitulate findings in the human disease [11].…”

Section: Introductionmentioning

confidence: 99%

Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

Donley¹,

Olson²,

Raisbeck³

et al. 2016

PLoS ONE

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.

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“…Additionally, symptoms of emotional dysregulation and increased inflammation can be detected decades before the onset of clinical symptoms in HD patients (Duff et al, 2007; Bjorkqvist et al, 2008; Politis et al, 2015). In fact, up to 60% of HD patients symptoms first begin with mental and emotional dysfunctions, which are often not immediately attributed to the disease (Di Maio et al, 1993; Pascu et al, 2015).…”

mentioning

confidence: 99%

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Raper

Bosinger²,

Johnson³

et al. 2016

Brain, Behavior, and Immunity

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Although the most notable clinical symptoms of Huntington’s disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (HD, n=2) as compared to wild-type controls (n=2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.

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Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers

Cited by 138 publications

References 51 publications

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

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