Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson’s disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson’s disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered.

Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.

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The aggregation of alpha-synuclein (a-syn) and immune activation are both pathological events related to the neurodegenerative process in Parkinson's disease (PD). The PD-associated immune response involves both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. CD163 is a scavenger receptor specifically expressed in the monocytic lineage, but normally not in microglia. Therefore, the presence of CD163 positive cells into the brain in PD rodent models and in PD patients suggest a monocytic infiltration or otherwise ectopic CD163 expression. In addition, changes in CD163 expression profiles observed in PD patients might indicate a role for CD163-expressing cells in the disease. To elucidate the relevance of the CD163 receptor in the a-syn-induced immune events in PD and associated degeneration we injected murine a-syn pre-formed fibrils (PFF), or monomeric a-syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of a-syn PFF in CD163KO females led to impaired early immune responses as revealed by the lack of ability to upregulate MHCII, CD68, GFAP, and promote CD4 and CD8 T cell infiltration after a-syn PFF injection. An early and long-lasting sensorimotor impairment was observed in a-syn PFF CD163KO males but not in the females. Transcriptomic analysis revealed that CD163 deletion induced phenotypic changes of macrophages and microglia in the brain that potentially impact the motor behavior and neuronal health induced by a-syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and a-syn pathology associated with autophagic defects, which ultimately led to increased dopaminergic neurodegeneration. Overall, our results support a novel sex-dimorphic neuroprotective role for CD163 in the a-syn-induced neuropathology and immune response.