Neuroinflammation and protein pathology in Parkinson’s disease dementia

Abstract

Parkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease

“…Studies in patients with PD have demonstrated blood–brain barrier compromise in the vicinity of the midbrain and increased T‐cells infiltrating affected brain regions 35 . CD4 + T‐cell counts in the amygdala correlate with activated microglia and alpha‐synuclein pathology, suggesting a causative role for infiltrating T‐cells in propagating neurodegeneration 36 . Thus, reductions in peripheral lymphocyte counts in incident PD may reflect migration of T‐cells into the central nervous system (CNS).…”

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

“…It is highly likely that S1-induced production of high concentrations of pro-inflammatory cytokines in the microglia results in neuronal damage and/or dysfunction in some of these CNS conditions. In Parkinson's disease for example, significant increase in the expression of IL-1β was shown in the substantia nigra and frontal cortex, compared to controls [33]. Pro-inflammatory cytokine (IL-1β, TNF-α, IL-6) release has also been linked to depression-like behaviours and cognitive defects in mice [34].…”

Neurodegenerative Disease and the NLRP3 Inflammasome

“…In PD, activated microglia have been found in the SN, and also in more widespread subcortical and cortical regions ( McGeer et al, 1988 ; Imamura et al, 2003 ; Kouli et al, 2020 ), and are implicated in neuronal toxicity, via secretions of inflammatory cytokines as well as inducing astrocytes to release neurotoxic elements ( Liddelow et al, 2017 ). Furthermore, in patients with PD, a pro-inflammatory profile of immune markers in the serum at diagnosis is linked to a faster subsequent decline in motor function and lower cognitive scores ( Williams‐Gray et al, 2016 ).…”

“…Furthermore, in patients with PD, a pro-inflammatory profile of immune markers in the serum at diagnosis is linked to a faster subsequent decline in motor function and lower cognitive scores ( Williams‐Gray et al, 2016 ). α-synuclein may play a critical role in driving peripheral immune activation in PD ( Sulzer et al, 2017 ; Scott et al, 2018 ; Schonhoff et al, 2020 ; Wijeyekoon et al, 2020 ), which may be associated with faster disease progression, presumably due to peripheral immune cells and cytokines crossing the blood brain barrier to promote microglial activation and neurotoxicity ( Figure 1 ) ( Kouli et al, 2020 ).…”