Microglial activation and dopamine terminal loss in early Parkinson's disease
ABSTRACT Neuroinflammatory glial response may contribute to degenerative processes in Parkinson's disease (PD). To investigate changes in microglial activity associated with changes in the presynaptic dopamine transporter density in the PD brain in vivo, we studied 10 early-stage drug-naive PD patients twice using positron emission tomography with a radiotracer for activated microglia [(11)C](R)-PK11195 and a dopamine transporter marker [(11)C]CFT. Quantitative levels of binding potentials (BPs) of [(11)C](R)-PK11195 and [(11)C]CFT in the nigrostriatal pathway were estimated by compartment analyses. The levels of [(11)C](R)-PK11195 BP in the midbrain contralateral to the clinically affected side were significantly higher in PD than that in 10 age-matched healthy subjects. The midbrain [(11)C](R)-PK11195 BP levels significantly correlated inversely with [(11)C]CFT BP in the putamen and correlated positively with the motor severity assessed by the Unified Parkinson's Disease Rating Scale in PD. In healthy subjects, the [(11)C](R)-PK11195 BP in the thalamus and midbrain showed an age-dependent increase. In vivo demonstration of parallel changes in microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathway in early PD supports that neuroinflammatory responses by intrinsic microglia contribute significantly to the progressive degeneration process of the disease and suggests the importance of early therapeutic intervention with neuroprotective drugs.
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- "These lines of evidence hint that synaptic í µí»¼-synuclein pathology could initiate and determine the onset of motor symptoms in PD. Indeed, clinical manifestations of the disease appear when dopamine levels in the striatum are reduced to 80% of normal levels, as measured by a decrease in [ 18 F] fluoro-DOPA PET binding, a consequence of dopamine neuron loss in substantia nigra   . Of note, this initial symptomatic phase is characterized by a significant worsening of putaminal presynaptic deficiency, with a marked reduction in dopamine presynaptic storage, transporter binding , and release  . "
ABSTRACT: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein α-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and α-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that α-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction and α-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.Parkinson's Disease 04/2015; 2015:1-10. DOI:10.1155/2015/108029 · 2.01 Impact Factor
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- "It has in fact long been recognized that PD brains are characterized by the presence of a microglial reaction (McGeer et al., 1988; McGeer and McGeer, 2004) which increases with disease duration (Croisier et al., 2005). Positron emission tomography studies have similarly reported increased microglial responses in early stages of the disease, correlating with severity of motor impairments (Ouchi et al., 2005). More targeted studies have revealed a possible role for toll-like receptors (TLRs) in the pathological processes underlying neurodegenerative disorders, including PD (Panaro et al., 2008; Ros-Bernal et al., 2011; Cote et al., 2011; Drouin-Ouellet et al., 2011; Drouin-Ouellet and Cicchetti, 2012; Kim et al., 2013;) For example, Syn can act as a DAMP for TLR2 (Kim et al., 2013) while TLR4 activation promotes microglial Syn clearance in synucleinopathies (Stefanova et al., 2011). "
ABSTRACT: Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson's disease (PD). Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the α-synuclein (αSyn) induced pathology seen in this condition. We used flow cytometry and western blots to detect toll-like receptor (TLR) 2 and 4 expression in blood and brain samples of PD patients and mice overexpressing human αSyn. To further assess the effects of αSyn overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-αSyn mice that expressed a bicistronic DNA construct (reporter genes luciferase) and green fluorescent protein) under the transcriptional control of the murine TLR2 promoter. Here, we report increases in TLR2 and TLR4 expression in circulating monocytes and of TLR4 in B cells and in the caudate/putamen of PD patients. Monthly bioluminescence imaging of Thy1.2-αSyn mice showed increasing TLR2 expression from 10 months of age, although no change in TLR2 and TLR4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for one month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test. Our results show that TLR2 and TLR4 are modulated in the blood and in the brain of PD patients and that overexpression of αSyn leads to a progressive microglial response, the inhibition of which as a beneficial impact on some motor phenotypes of an animal model of α-synucleinopathy. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 12/2014; 18(6). DOI:10.1093/ijnp/pyu103 · 4.01 Impact Factor
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- "Microglia is activated in the presence of aggregated forms of α-synuclein (Zhang et al., 2005), expressing macrophage markers and releasing IL-1β, IL-6 and TNF-α which can damage the DAc (Croisier et al., 2005; Orr et al., 2005). This activation has been found in both PD (Hunot et al., 1996; Knott et al., 2000) and aged brains (Godbout and Johnson, 2004; Gelinas and McLaurin, 2005; Campuzano et al., 2009), suggesting that the neurotoxic action of these cells is similar in both conditions (Ouchi et al., 2005; Streit et al., 2008; Cunningham, 2013). "
ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.Frontiers in Neuroanatomy 08/2014; 8:80. DOI:10.3389/fnana.2014.00080 · 3.54 Impact Factor