Abstract
Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson’s disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another brain region, like the hippocampus (HC), which is implicated in dementia and depression, important non-motor symptoms in PD.We studied phenotypes and activation of microglia in the SN and HC of established PD patients (Braak PD stage 4–6), matched controls (Braak PD stage 0) and of incidental Lewy Body disease (iLBD) cases (Braak PD stage 1–3) that are considered a prodromal state of PD. As recent experimental studies suggested that toll-like receptor 2 (TLR2) mediates α-synuclein triggered microglial activation, we also studied whether TLR2 expression is indeed related to pathology in iLBD and PD patients.A clear α-synuclein pathology-related increase in amoeboid microglia was present in the HC and SN in PD. Also, morphologically primed/reactive microglial cells, and a profound increase in microglial TLR2 expression were apparent in iLBD, but not PD, cases, indicative of an early activational response to PD pathology. Moreover, TLR2 was differentially expressed between the SN and HC, consistent with a region-specific pattern of microglial activation.In conclusion, the regional changes in microglial phenotype and TLR2 expression in primed/reactive microglia in the SN and HC of iLBD cases indicate that TLR2 may play a prominent role in the microglial-mediated responses that could be important for PD progression.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects 1–2% of the elderly population [1]
PD patients showed extensive loss of neuromelanincontaining, dopaminergic neurons in the substantia nigra (SN), and the number of Lewy bodies (LBs) and Lewy neurites (LN) was significantly increased compared to both control and incidental Lewy Body disease (iLBD) cases (Figure 1c; Figure 2a; PD vs Ctr/iLBD p < 0.01; Ctr n = 13, Mean = 0 ± 0; iLBD n = 9, Mean = 7 ± 6.2; PD n = 14, Mean = 29.2 ± 4.9)
In PD patients, toll-like receptor 2 (TLR2) IR remained upregulated in the SN, but was reduced to control levels in the HC
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects 1–2% of the elderly population [1]. Besides classical motor problems that are related to nigro-striatal dopamine deficits [2], nonmotor symptoms are common in PD These include autonomic dysfunction, sensory, sleep and cognitive disturbances as well as neuropsychiatric alterations, that. Microglial cells readily transform from a ramified morphology into amoeboid-shaped cells. They acquire specific functions, including phagocytosis, and can secrete a variety of factors, such as cytokines, chemokines, reactive oxygen species (ROS) and trophic factors [14,15]. In contrast to the SN, it is not associated with neuronal cell death [23] These observations agree with novel views on microglia as a heterogeneous cell population that may exert brain regiondependent functions [13,25,26,27]. Microglia are thought to contribute to local inflammatory responses, not in a uniform, but rather in a brain region-specific manner
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