Parkinson's disease is characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the cause of the neuronal loss in Parkinson's disease is poorly understood. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. In this Review, we describe the evidence for neuroinflammatory processes from post-mortem and in vivo studies in Parkinson's disease. We further identify the cellular and molecular events associated with neuroinflammation that are involved in the degeneration of dopaminergic neurons in animal models of the disease. Overall, available data support the importance of non-cell-autonomous pathological mechanisms in Parkinson's disease, which are mostly mediated by activated glial and peripheral immune cells. This cellular response to neurodegeneration triggers deleterious events (eg, oxidative stress and cytokine-receptor-mediated apoptosis), which might eventually lead to dopaminergic cell death and hence disease progression. Finally, we highlight possible therapeutic strategies (including immunomodulatory drugs and therapeutic immunisation) aimed at downregulating these inflammatory processes that might be important to slow the progression of Parkinson's disease.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442209700626.pdf

Neuroinflammation in Parkinson's disease: a target for neuroprotection?

https://www.cell.com/neuron/pdf/S0896-6273(02)00794-8.pdf

Inflammation in Neurodegenerative Disease—A Double-Edged Sword

It has been a long standing hypothesis that blood tissue of PD Parkinson's disease (PD) patients may exhibit signs of accelerated aging. Here we use DNA methylation based biomarkers of aging ("epigenetic clock") to assess the aging rate of blood in two ethnically distinct case-control data sets. Using n=508 Caucasian and n=84 Hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (IEAA), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (EEAA) which is associated with age dependent changes in blood cell counts. Blood of PD subjects exhibits increased age acceleration according to both IEAA (p=0.019) and EEAA (p=6.1 x 10(-3)). We find striking differences in imputed blood cell counts between PD cases and controls. Compared to control subjects, PD subjects contains more granulocytes (p=1.0 x 10(-9) in Caucasians, p=0.00066 in Hispanics) but fewer T helper cells (p=1.4 x 10(-6) in Caucasians, p=0.0024 in Hispanics) and fewer B cells (p=1.6 x 10(-5) in Caucasians, p=4.5 x 10(-5) in Hispanics). Overall, this study shows that the epigenetic age of the immune system is significantly increased in PD patients and that granulocytes play a significant role.

/pdf/increased-epigenetic-age-and-granulocyte-counts-in-the-blood-3un6fhx4cc.pdf

Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients

Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease

Progressive loss of dopaminergic neurons in the substantia nigra pars compacta and their terminal connections in the striatum are central features in Parkinson's disease (PD). Emerging evidence supports the notion that microglia neuroinflammatory responses speed neurodegenerative events. We demonstrated previously that this can be slowed by adoptive transfer of T cells from Copolymer-1-immunized mice administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) recipients. The cellular basis for this neuroprotective response was the CD4+ T cell population, suggesting involvement of CD4+CD25+ regulatory T cells (Tregs), cells known to suppress immune activation and maintain immune homeostasis and tolerance. We show for the first time that adoptive transfer of CD3-activated Tregs to MPTP-intoxicated mice provides greater than 90% protection of the nigrostriatal system. The response was dose-dependent and paralleled modulation of microglial responses and up-regulation of glial cell-derived neurotrophic factor (CDNF) and TGF-beta. Interestingly, that adoptive transfer of effector T cells showed no significant neuroprotective activities. Tregs were found to mediate neuroprotection through suppression of microglial responses to stimuli, including aggregated, nitrated alpha-synuclein. Moreover, Treg-mediated suppression was also operative following removal of Tregs from culture prior to stimulation. This neuroprotection was achieved through modulation of microglial oxidative stress and inflammation. As Tregs can be modulated in vivo, these data strongly support the use of such immunomodulatory strategies to treat PD.

Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease.

Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism.

Apoptosis of peripheral blood lymphocytes in Parkinson patients.

To assess the involvement of the immune system in Parkinson's disease we studied the phenotype of circulating lymphocytes in 30 11 1 1 untreated and 34 treated patients. We found a numeric decrease in helper T cells (higher in CD4 CD45RA than in CD4 CD29 ) and B 11 cells, and a rise in activated, CD4 CD25 lymphocytes that was correlated with lymphocyte depletion. All these alterations were 1 independent of levodopa treatment. In addition, we performed striatal dopamine depletion in rats with either MPP or 6-OHDA, showing 11 1 that MPP but not 6-OHDA can increase CD4 CD25 lymphocytes. Thus, mechanisms other than dopamine deficit may explain the immune activation in Parkinson's disease. © 2001 Elsevier Science B.V. All rights reserved.

Màtil Calopa

Papers

Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism.

Apoptosis of peripheral blood lymphocytes in Parkinson patients.

Lymphocyte populations in Parkinson's disease and in rat models of