Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Vitola, Pietro La; Balducci, Claudia; Cerovic, Milica; Santamaria, Giulia; Brandi, Edoardo; Grandi, Federica; Caldinelli, Laura; Colombo, Laura; Morgese, Maria Grazia; Trabace, Luigia; Pollegioni, Loredano; Albani, Diego; Forloni, Gianluigi

doi:10.1016/j.bbi.2018.02.012

Cited by 59 publications

(71 citation statements)

References 47 publications

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“…32 Although inflammatory features have been described in patients with both synucleinopathies and tauopathies, by PET studies, [33][34][35][36] from Toll-like receptor 4. 37,38 Moreover a recent multicenter study has shown higher levels of CSF inflammatory biomarkers in PD with dementia and MSA compared with controls and not in AP-Tau vs controls, plus those markers correlated with motor and cognitive impairment. 39 Likewise, our analysis showed a moderate correlation between CD25, CD146, and cognitive impairment in PD suggesting a link between inflammation and a major cognitive decline: CD25 is a costimulatory molecule supporting immune cell activation, 40 and CD146 acts as an essential regulator of pericyte-endothelial cell communication in the blood-brain barrier and it has been identified as a potential key therapeutic target for cerebrovascular disorders.…”

Section: Discussionmentioning

confidence: 99%

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

Vacchi

Burrello

Silvestre

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform.MethodsPlasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort.ResultsDistinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations.ConclusionsImmune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP.

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Section: Discussionmentioning

confidence: 99%

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

Vacchi

Burrello

Silvestre

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…PrP106‐126 and other amyloidogenic PrP peptides continue to serve as useful tools for investigating the cellular and molecular pathogenesis of prion diseases and to screen for new neuroprotective compounds. We recently developed a simple in vivo model in which acute intraventricular injection of Aβ or α‐synuclein oligomers caused cognitive deficits in mice . Both Aβ and α‐synuclein oligomers caused recognition memory impairment and glial activation through distinct molecular mechanisms.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Review: PrP 106‐126 – 25 years after

Forloni

Chiesa

Bugiani

et al. 2019

Neuropathology Appl Neurobio

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A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106‐126 of the human prion protein (PrP106‐126), a sequence present in the PrP amyloid protein of Gerstmann–Sträussler–Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106‐126 contributed to underpin the role of amyloid in the pathogenesis of protein‐misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion‐like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106‐126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106‐126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later.

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“…Moreover, the relationship among neurons and other cells such as microglia and astrocytes is complex in the pathology of brain diseases [64,65]. For instance, La et al found that alpha-synuclein oligomers activating glial cells led to neuron damage and thus were emerging as crucial factors in the pathogenesis of synucleinopathies [66]. Wang et al reported that HAPLN2 involved in the pathogenesis of schizophrenia by regulating the neuron migration and velocity of nerve conduction [67].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-7, synergizes with RORα, negatively controls the pathology of brain tissue inflammation

Yue

Zhao

Chen

et al. 2020

J Neuroinflammation

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Background: Accumulating evidence has documented that microRNA-7 (miR-7) plays an important role in the pathology of various diseases. However, the potential role of miR-7 in brain tissue inflammation (BTI) remains unclear. Methods: We detected the expression of miR-7 in LPS-induced murine BTI model and observed the possible effects of miR-7 deficiency on the pathology of BTI. To elucidate the mechanism, the target gene of miR-7 was screened out by Gene chip assay and its potential roles in BTI were evaluated by Western blot, immunofluorescence, and RNAi assay, respectively.Results: MiR-7 was upregulated in brain tissue in BTI mice and its deficiency could significantly aggravate the pathology of brain tissue. Moreover, RORα, a new target molecule of miR-7, was upregulated in brain tissue from miR-7 deficiency BTI mice. Of note, downregulation of RORα could remarkably exacerbate the pathology of brain tissue and elevate the transduction of NF-κB and ERK1/2 signaling pathways in brain tissue from miR-7 deficiency BTI mice. Furthermore, RORα and miR-7 were dominantly co-expressed in neurons of BTI mice. Finally, RORα synergized with miR-7 to control the inflammatory reaction of neuronal cells in response to LPS stimulation.Conclusions: MiR-7 expression is upregulated in BTI model. Moreover, miR-7 synergizes with its target gene RORα to control the inflammation reaction of neurons, thereby orchestrating the pathology of BTI.

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Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Cited by 59 publications

References 47 publications

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

Review: PrP 106‐126 – 25 years after

MicroRNA-7, synergizes with RORα, negatively controls the pathology of brain tissue inflammation

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