Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

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.

Distinct Pattern of Microgliosis in the Olfactory Bulb of Neurodegenerative Proteinopathies

“…This is in accordance with recent data showing increased microglial proliferation in the temporal cortex of AD brains, mediated by the activity of the colony stimulating factor 1 receptor signaling pathway [55]. Interestingly, our findings in PDD/DLB relate well to data showing increased microglia proliferation in the hippocampus only in presymptomatic incidental Lewy body disease, but not in defined PD patients [33], similar to an increased toll-like receptor 2 expression in the hippocampus of incidental Lewy body disease only [56]. These findings may indicate that proliferation of microglia, in particular in synucleinopathies, might be an early event, possibly declining towards more advanced stages of the disease.…”

Molecular changes in the postmortem parkinsonian brain

“…), and microglial activation (Doorn et al . ). However, few studies have focused on the molecular changes.…”

“…Incidental Lewy body disease (ILBD) is usually considered as a prodromal state of PD characterized by the absence of motor symptoms, but the presence of a variety of non-motor abnormalities. At the cellular level, ILBD is characterized by a moderate nigral neuronal loss (Dijkstra et al 2014) and Lewy pathology (Iacono et al 2015), decreased striatal dopaminergic immunoreactivity (Beach et al 2008;Delle-Donne et al 2008;Dickson et al 2008), olfactory bulb abnormalities (Driver-Dunckley et al 2014), and microglial activation (Doorn et al 2014). However, few studies have focused on the molecular changes.…”

The Indispensable Roles of Microglia and Astrocytes during Brain Development

“…Apart from temporal differences in gene expression profiles, region-specific differences have also been found (Doorn et al, 2015; Matcovitch-Natan et al, 2016). Also, distinct types of microglia were found to be present in different brain regions and have been implicated in neuropathological disorders such as Parkinson’s disease (Doorn et al, 2012, 2014, 2015), which could have a developmental origin. The above described studies suggest that together with the intrinsic properties of the microglia, local environmental factors determine the phenotypic characteristics and functions of microglia during embryonic development of the brain.…”