Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2

Abstract

Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson’s disease (PD). Cell-to-cell propagation of α-synuclein (α-syn) pathology is a highlighted feature of PD, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of α-syn pathology. Recent data revealed that plasma exosomes derived from PD patients (PD-EXO) carry pathological α-syn and target microglia preferentially. Hence, PD-EXO is likely a key tool for investigating the role of microglia in α-syn transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal α-syn from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal α-syn and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous α-syn in the substantia nigra (SN). Furthermore, exosomal α-syn internalization was initiated by binding to TLR2 of microglia. Excessive α-syn phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated α-syn pathology in vivo. Overall, the present data support the idea that the interaction of exosomal α-syn and microglial TLR2 contribute to excessive α-syn phagocytosis and microglial activation, which lead to the further propagation and spread of α-syn pathology, thereby highlighting the pivotal roles of reactive microglia in α-syn transmission.

COVID-19 leukoencephalopathy with subacute magnetic resonance imaging findings of vasculitis and demyelination

“…In addition, the clinical presentation was in contrast to our critically ill patient with poor neurological status; the latter is the emerging phenotype of COVID-19 leukoencephalopathy (Novi et al 2020 ). Of note, reports in the COVID-19 pandemic of other parainfectious immune-mediated neurological conditions such as cytotoxic lesions of the corpus callosum and Guillain-Barré syndrome remain relatively sparse considering the worldwide prevalence (Xiong et al 2021 ). However, that does not discount ADEM as a possibility in our case where a clinical response was seen following immunotherapy.…”

“…A wide spectrum of neurological disease is recognized in COVID-19 from mild to severe presentations (Mao et al 2020 ; Xiong et al 2021 ). We report two patients with severe respiratory failure and poor neurological status with novel subacute radiological findings that yield insight into the pathogenesis of COVID-19 leukoencephalopathy.…”

Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy

“…TLR2. 94 Recently, Izco et al 95 investigated the temporal relationship between αSyn and inflammation in a mouse model of PD. They found that the peak expression of Iba1-positive microglia, GFAP-positive astrocytes, and IL-1β occurred before αSyn accumulation.…”

“…Furthermore, several researchers have been able to block or suppress microglial activation using pharmacological drugs and thereby have identified decreases in αSyn pathology in a mouse model. 17,94 There is also evidence that astrocytes actively transfer aggregated αSyn to healthy astrocytes through direct contact or tunneling nanotubes. 41,96 Ngolab et al 97 demonstrated that DLB brainderived exosomes trigger αSyn accumulation in astrocytes in the mouse brain, suggesting the participation of astrocytes in αSyn transmission.…”

Glycation renders ɑ-synuclein oligomeric strain and modulates microglia activation

“…During neuronal transmission of α-synuclein, microglia senses, engulfs and clears the extracellular α-synuclein to maintain the homeostasis in the brain (30,31). Several microglial receptors such as TLR2, TLR4, CD11b, FcγRIIB have been reported to interact with αsynuclein and its strains further induce pro-inflammatory microglia response [32,33,34,35].…”