The choreography of neuroinflammation in Huntington's disease

Crotti, Andrea; Glass, Christopher K.

doi:10.1016/j.it.2015.04.007

Cited by 209 publications

(168 citation statements)

References 107 publications

(164 reference statements)

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“…Using flow cytometry combined to the fluorescent membrane probe 8-anilino-l-naphthalene sulfonate (ANS), they observed an increase in ANS fluorescence intensity in lymphocytes harvested from patients with HD in comparison with controls [33]. Decades later, studies confirmed this hypothesis, showing that mutant HTT can be found in several cells types, including lymphocytes [6]. …”

Section: Peripheral 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: Peripheral 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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“…Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5)(6)(7)(8)(9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5,8), but key questions remain unanswered (2,(13)(14)(15).…”

mentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…The role of kynurenine catabolism in the regulation of the immune response is important, and this is difficult to evaluate in mouse models of HD. We therefore consider that the role of Quin elevation and dysregulation of KMO activity in neurodegeneration and neuro-inflammation is worth testing in conditions displaying significant neuronal cell loss and glial activation, including in HD patients (Crotti and Glass, 2015;Tai et al, 2007;Waldvogel et al, 2015). We are in the process of independently assessing whether levels of KP metabolites are altered in the CSF of clinically well-characterized HD patients.…”

Section: Discussionmentioning

confidence: 99%