Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease

Harms, Ashley S.; Thome, Aaron D.; Yan, Zhaoqi; Schonhoff, Aubrey M; Williams, Gregory P.; Li, Xinru; Liu, Yudong; Qin, Hongwei; Benveniste, Etty N.; Standaert, David G.

doi:10.1016/j.expneurol.2017.11.010

Cited by 181 publications

(167 citation statements)

References 64 publications

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“…Our data are in line with other studies reporting peripheral inflammation in PD, including changes in patients' blood immune cells [60][61][62] . Of note, the reduction of peripheral monocytes in Syn rats might explain the increased Iba1 + cell numbers in SNpc, striatum and hippocampus, given that both resident microglia and infiltrated monocyte-derived macrophages can express Iba1, in line with recent evidence of monocyte, T-or B-cell infiltration in α-syn based models [63][64][65][66] . Nonetheless, we cannot exclude other possible explanations for blood monocyte reduction in Syn rats, including cell death following inflammatory activation or re-mobilization from primary/secondary lymphoid organs, including bone marrow and spleen, where they are recruited for clearance.…”

Section: Discussionsupporting

confidence: 58%

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

et al. 2019

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Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

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Section: Discussionsupporting

confidence: 58%

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

et al. 2019

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“…NGAL (or lipocalin-2) has shown to heighten the sensitivity of neurons to amyloid beta toxicity in murine primary cortical cultures (Naude et al, 2012). While, CCL2 signaling recruits peripheral immune cells into the brain, and the crossing of peripheral monocytes has shown to be detrimental as demonstrated in animals models of multiple sclerosis and PD (Ajami et al, 2011;Harms et al, 2018); however, their exact role in the CNS is not clear.…”

Section: Sex-specific Immune Responses To Mptpmentioning

confidence: 99%

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

Joers

Masilamoni

Kempf

et al. 2020

Preprint

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Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [ 18 F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

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“…In particular, growing evidence shows distinct inflammatory reactions in the pathogenesis of PD [122]. Recruitment of peripheral immune cells, reactive microgliosis, and increased pro-inflammatory mediators are observed in the brain of PD patients and in animal model of PD [123][124][125]. In an intra-nigrally α-synuclein-injected model of PD, α-synuclein was shown to induce the infiltration of peripheral myeloid cells into the CNS, which have pro-inflammatory properties [123].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

Cheon

Kim

et al. 2020

IJMS

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Cognitive symptoms are prevalent in the elderly and are associated with an elevated risk of developing dementia. Disease-driven changes can cause cognitive disabilities in memory, attention, and language. The inflammasome is an innate immune intracellular complex that has a critical role in the host defense system, in that it senses infectious pathogen-associated and endogenous danger-associated molecular patterns. An unbalanced or dysregulated inflammasome is associated with infectious, inflammatory, and neurodegenerative diseases. Due to its importance in such pathological conditions, the inflammasome is an emerging drug target for human diseases. A growing number of studies have revealed links between cognitive symptoms and the inflammasome. Several studies have shown that reducing the inflammasome component mitigates cognitive symptoms in diseased states. Therefore, understanding the inflammasome regulatory mechanisms may be required for the prevention and treatment of cognitive symptoms. The purpose of this review is to discuss the current understanding of the inflammasome and its relationships with cognitive symptoms in various human diseases.

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Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease

Cited by 181 publications

References 64 publications

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

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