Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease

Bouchard, Jill; Truong, Jennifer; Bouchard, Kristofer E.; Dunkelberger, Diana; Desrayaud, Sandrine; Moussaoui, Saliha; Tabrizi, Sarah J.; Stella, Nephi; Muchowski, Paul J.

doi:10.1523/jneurosci.4008-12.2012

Cited by 113 publications

(85 citation statements)

References 58 publications

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“…Genetic deletion of cannabinoid receptor 2 (CB2) -a protein expressed predominantly in peripheral immune cells that regulates production of proinflammatory cytokines, likely via NF-κB (65-67) -exacerbates pathogenesis in a mouse model of HD (68). Consistent with these findings, we recently found that CB2 signaling in immune cells mediates the onset and severity of symptoms in BACHD mice and that CB2 agonists are neuroprotective in R6/2 mice, even when given at late disease stages (69). Finally, inhibition of kynurenine 3-monooxygenase (KMO) in blood cells prevented synaptic loss and brain inflammation and increased lifespan in R6/2 mice (56).…”

Section: Figurementioning

confidence: 68%

Mutant huntingtin impairs immune cell migration in Huntington disease

Kwan¹,

et al. 2012

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In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

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Section: Figurementioning

confidence: 68%

Mutant huntingtin impairs immune cell migration in Huntington disease

Kwan¹,

et al. 2012

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“…However, as recent study unequivocally demonstrated that CB 1 R-dependent neuroprotective activity in HD is predominantly derived from a restricted population of these receptors on cortical glutamatergic neurons that project to the striatum and that are preserved during the progression of HD rather than from the CB 1 R located on striatal projection γ-aminobutyric acid (GABA)-ergic neurons that are progressively lost during disease progression [142], supporting the relevance of these receptors as potential targets for a neuroprotective therapy with cannabinoids in HD. In addition, the benefits found after CB 2 R activation in HD may be facilitated by overexpression of these receptors in the striatal parenchyma, an effect that was first detected when striatal damage was provoked in rats with malonate [134], and in R6/2 mice and other genetic mouse models of HD [135,143], as well as in postmortem tissues from patients with HD [134]. This upregulation appears to occur in astrocytes [134] (although no CB 2 R expression was found in these glial cells in human HD tissues [144]) and particularly in reactive microglia [134,135].…”

Section: Cannabinoids and Chronic Neurodegenerative Disorders: III Hdmentioning

confidence: 99%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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“…Inflammatory reactions, specifically microglial activation and/or cytokine release, have been described in brains of HD patients (Sapp et al, 2001;Pavese et al, 2006;Silvestroni et al, 2009) and mouse models (Bjorkqvist et al, 2008;Bouchard et al, 2012;Kwan et al, 2012), including R6/2 mice Wacker et al, 2009), and may contribute importantly to the progression of the disease (Möller, 2010). We evaluated the effect of LM22A-4 on inflammation, as assessed with immunostaining for IBA-1, a protein expressed by activated or proliferating microglia (Ridley et al, 1992;Imai et al, 1996;Ito et al, 1998), that is increased in R6/2 brains Wacker et al, 2009).…”

Section: Lm22a-4 Decreases Inflammation In the Striatum Of R6/2 Micementioning

confidence: 99%

A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease

Simmons¹,

et al. 2013

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Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75 NTR , could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLC␥, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.

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Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease

Cited by 113 publications

References 58 publications

Mutant huntingtin impairs immune cell migration in Huntington disease

Mutant huntingtin impairs immune cell migration in Huntington disease

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease

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