Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation

Zhang, Qiu-Shuang; Heng, Yang; Yuan, Yu‐He; Chen, Nai‐Hong

doi:10.1016/j.toxlet.2016.11.002

Cited by 123 publications

(93 citation statements)

References 97 publications

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“…This was corroborated by reported data from a rat model of PD, where the activation of microglia seems to precede dopaminergic neuronal cell loss [56]. Given the fact that a chronological spread of LB inclusions occurred in α-synucleinopathies [57], and these α-synuclein can directly provoke microglial activation [58], we could expect to find, in a time-dependent fashion, a widespread TSPO signal in PET imaging. Interestingly, Gerhard and colleagues [51] reported a lack of change in levels of cortical and subcortical TSPO tracer uptake for two years, despite the clinical deterioration of PD patients.…”

Section: Clinical Input Of Tspo Pet Imaging In Neurodegenerative Dsupporting

confidence: 80%

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

Dupont

Largeau

Ribeiro

et al. 2017

IJMS

142

116

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In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

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Section: Clinical Input Of Tspo Pet Imaging In Neurodegenerative Dsupporting

confidence: 80%

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

Dupont

Largeau

Ribeiro

et al. 2017

IJMS

142

116

View full text Add to dashboard Cite

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“…The greater expression of α-synuclein in remaining TH-positive cells of lesion non-VNS rats indicates that either protein transport to the terminal is dysfunctional, or the cells are unable to degrade the additional α-synuclein in cell bodies as they normally would [36], demonstrating an expression pattern similar to that of PD patients [52,54]. Previous studies have also shown that increases in α-synuclein expression can increase microglial activation and may contribute to inflammation [55]. Thus, VNS treatment results in reduced α-synuclein in TH-positive neurons that may be in part due to the anti-inflammatory properties of VNS (further discussed below), although future studies must be conducted to determine the relationship between inflammation and α-synuclein in this model.…”

Section: Discussionmentioning

confidence: 99%

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

et al. 2017

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Background Parkinson’s disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. Objective To assess therapeutic potential of VNS in a PD model. Methods To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). Results VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Conclusions Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic.

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“…One of the most important signaling pathways associated with the microglial activation in PD involves nuclear factor-kappa B (NF-kB) (Zhang et al, 2017). The activation of this factor could increase the release of proinflammatory cytokines such TNF-α and interleukin 1β by microglial cells (Mogi et al, 1996; McLaughlin et al, 2006).…”

Section: Parkinson and Microgliamentioning

confidence: 99%

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma

Ramírez

Hoz

Salobrar‐García

et al. 2017

Front. Aging Neurosci.

353

339

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Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration.

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Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation

Cited by 123 publications

References 97 publications

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma

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