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 01/2015; 2015:1-10. DOI:10.1155/2015/108029
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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
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- "However, characterization of the PPP in our experiments has shown that NADPH production is not increased in the putamen of samples with early stage PD and furthermore, PPP enzyme levels are actually decreased. This is despite widely documented evidence that dopaminergic cell death in the striatum of PD cases is accompanied by increased markers for oxidative stress and neuroinflammation in postmortem samples (Alam et al., 1997; Imamura et al., 2003; Marttila et al., 1988; Ouchi et al., 2005; Sanchez-Ramos et al., 1994) and in vivo, by positron emission tomography imaging studies (Ikawa et al., 2011). Similarly, although there are a number of published studies showing increased levels of oxidative stress in the frontal cortex of cases with both clinical and preclinical PD (Dalfo et al., 2005; Ferrer, 2009; Parker et al., 2008), the early stage cases in our experiments again did not show an increase in NADPH levels. "
ABSTRACT: Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.Neurobiology of aging 11/2013; 35(5). DOI:10.1016/j.neurobiolaging.2013.11.001