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Figure 1. Aging in combination with the particular vulnerability of the dopaminergic system contributes to the pathogenesis of PD. Dopaminergic neurons in the substantia nigra are particularly vulnerable to aging-related alterations in cell metabolism. The sheer size of their axonal arbor in comparison to the soma, and their tonic activity with high cytosolic calcium fluctuation demand high levels of energy for maintenance. Aging-associated mitochondrial insufficiency, impaired protein turnover, and aggregation of proteins lead to additional cell stress via ROS and the accumulation of toxic dopamine metabolites pushing dopamine neurons over the brink of their fragile homeostatic equilibrium. The degeneration of dopaminergic neurons in turn will result in the activation of residing immune cells (microglia), which themselves, with age, tend to present a more pro-inflammatory phenotype, which can perpetuate a hostile environment for neurons. On the other hand, aging itself leads to increased inflammatory microglial phenotype with reduced phagocytic capacity, which attracts peripheral lymphocytes, thereby maintaining an inflammatory environment. With age, parenchymal microglia are also increasingly replaced by peripherally recruited myeloid macrophages, which also tend to have a more pro-inflammatory phenotype. The same is true for the second important tissue-resident macrophage population of the brain, BAMs in the perivascular and meningeal space. Vessel-associated microglia and BAMs, in addition to their immunological role, are essential for the integrity of the BBB and control of its permeability through direct actions as well as by influencing vascular tone. The BBB itself is influenced by aging and is likely to be involved in PD pathogenesis. Aging-related changes of the BBB include a loss of pericyte and endothelial tight junctions, increasing the leakiness of peripheral cytokines and toxins. In addition, BECs upregulate VCAM1, which promotes the binding of circulating immune cells, inducing local inflammation. Furthermore, BECs lose their capacity for selective receptor-mediated transport of plasma proteins with age, which could negatively influence the microenvironment of dopaminergic neurons. The aging of the immune system itself is likely caused by the involution of the thymus with a reduction of naïve immune cells and an expansion of polyclonal antigen-experienced T cells triggered by recurrent life-long exposure to common pathogens (e.g., CMV). These senescent immune cells display a common senescent phenotype with enhanced secretion of pro-inflammatory cytokines sustaining a chronic low-grade inflammation (inflammaging). With age, the homeostatic T cell proliferation as a statistical process might as well lead to the selection of T cells with increased affinity to self- or neoantigens (as proposed in PD pathogenesis), facilitating autoimmune responses. Furthermore, regulatory inflammation-limiting and autotolerance-promoting populations of Tregs are diminished in relation to effector T cells. This figure represents a schematic overview and more detailed explanations and references can be found in the main body of the article. Created with BioRender.com. PD: Parkinson’s disease; ROS: reactive oxygen species; BAMs: border-associated macrophages; BBB: blood-brain barrier; BEC: brain endothelial cell; VCAM1: vascular cell adhesion molecule 1; CMV: cytomegalovirus; α-syn: α synuclein; CNS: central nervous system;
