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

Abstract

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.

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…HD patients show a positive pro-inflammatory profile (Figure 1) correlated with the disease's progression, including increases of IL-1β, IL-6, and TNF-α in the striatum, cerebral spinal fluid and plasma that were also confirmed in mouse models (Rocha et al, 2016). Central immune activation in HD subjects was confirmed using positron emission tomography (PET) and in pre-symptomatic HD-gene carriers (Rocha et al, 2016). Even though pharmacologic immune modulation using the XPro1595 TNF-α inhibitor has shown neuroprotection against the cytokine-induced neurotoxicity in primary R6/2 neurons and human neurons derived from iPSCs of HD patients (Hsiao et al, 2014), the information available is contradictory based on one report describing that neuroinflammation seems a consequence rather than a cause of neurodegeneration in late HD (Vinther-Jensen et al, 2016).…”

“…Huntington's disease is an autosomal-dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion that gives place to a polyglutamine region in the huntingtin protein (HTT). HD patients show a positive pro-inflammatory profile (Figure 1) correlated with the disease's progression, including increases of IL-1β, IL-6, and TNF-α in the striatum, cerebral spinal fluid and plasma that were also confirmed in mouse models (Rocha et al, 2016). Central immune activation in HD subjects was confirmed using positron emission tomography (PET) and in pre-symptomatic HD-gene carriers (Rocha et al, 2016).…”

Drumming motor sequence training induces apparent myelin remodelling in Huntington’s disease: a longitudinal diffusion MRI and quantitative magnetization transfer study

“…MPF can also be affected by inflammation (Henkelman, Stanisz, & Graham, 2001) and in manifest HD it is likely that inflammation goes hand in hand with myelin breakdown (Rocha et al, 2016). However, a recent CSF biomarker study found no evidence of neuro-inflammation in early-manifest HD (Vinther-Jensen et al, 2016).…”

Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease

“…In addition, inflammation has now been shown to be important in many chronic neurodegenerative disorders of the brain such as Alzheimer's disease (AD) and Parkinson's disease as well as HD . The evidence for a key role of inflammation to HD comes from studies looking at microglial activation on imaging and pathologically as well as peripheral cytokine profiles, which can be found early on in the disease.…”

“…[19][20][21] In addition, inflammation has now been shown to be important in many chronic neurodegenerative disorders of the brain such as Alzheimer's disease (AD) 22 and Parkinson's disease 23 as well as HD. 24 The evidence for a key role of inflammation to HD comes from studies looking at microglial activation on imaging and pathologically 25 as well as peripheral cytokine profiles, 26 which can be found early on in the disease. Inflammation-related genetic modifiers have also been shown to influence the risk of developing neurodegenerative disorders such as sporadic AD, and this includes the triggering receptor expressed on myeloid cells 2 (TREM2) [27][28][29][30][31][32][33] and toll-like receptor 4 (TLR4).…”