Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

Iba, Michiyo; Kim, Changyoun; Sallin, Michelle; Kwon, Somin; Verma, Amita; Overk, Cassia R.; Rissman, Robert A.; Sen, Ranjan; Sen, Jyoti Misra; Masliah, Eliezer

doi:10.21203/rs.3.rs-21922/v1

Cited by 4 publications

(3 citation statements)

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“…T lymphocytes are altered and infiltrate the brain in PD [22][23][24][25][26][27][28][29] and it has been reported that autoreactive T lymphocytes directed against ␣-syn are present in PD patients [30] decades prior to motor PD [31]. Recruitment of CD4 + T cells to the brain occurs in models of a-syn overexpression [32]. In PD models, T cell function has been linked to ␣-syn pathobiology [33][34][35] and to the death of dopamine neurons [8,36].…”

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confidence: 99%

T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils

George

Tyson

Rey

et al. 2021

JPD

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Background: α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of α- synucleinopathies, such as Parkinson’s disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease. Objective To study the role of the adaptive immune system with respect to α-syn pathology. Methods: We injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology, proteinase K-resistant α-syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naïve T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated α-syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice. Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental α-synucleinopathy.

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confidence: 99%

T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils

George

Tyson

Rey

et al. 2021

JPD

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“…Numerous studies have demonstrated T cell involvement in the pathophysiology of PD. T cells infiltrate into the brain in different animal models of PD, including 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in mice and rats (Theodore and Maragos, 2015;Ambrosi et al, 2017), the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mouse (Reynolds et al, 2010;González et al, 2013), human α-synuclein (α-syn)overexpressing transgenic mice (hαSyn, Thy1-SNCA) (Sommer et al, 2016;Iba et al, 2020). Other studies demonstrated that T celldeficient mice were resistant to MPTP-induced neurodegeneration (Benner et al, 2008;Brochard et al, 2009;González et al, 2013).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Meningeal T cells function in the central nervous system homeostasis and neurodegenerative diseases

Abbaoui

Fatoba

Yamashita

2023

Front. Cell. Neurosci.

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Recently, a rising interest is given to neuroimmune communication in physiological and neuropathological conditions. Meningeal immunity is a complex immune environment housing different types of immune cells. Here, we focus on meningeal T cells, possibly the most explored aspect of neuro-immune cell interactions. Emerging data have shown that meningeal T cells play a crucial role in the pathogenesis of several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review highlights how meningeal T cells may contribute to immune surveillance of the central nervous system (CNS) and regulate neurobehavioral functions through the secretion of cytokines. Overall, this review assesses the recent knowledge of meningeal T cells and their effects on CNS functioning in both health and disease conditions and the underlying mechanisms.

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“…LB pathology was originally found in axons before becoming evident in neuronal soma, called "Lewy neurites" (LN; Koch et al, 2015). LB and LN are composed mainly of aggregated α-synuclein (α-Syn), a protein normally found pre-synaptically (Iba et al, 2020) that misfolds when phosphorylated at serine 129 (pS129; Hirai et al, 2004). Abnormal accumulation of α-Syn triggers the death of dopaminergic neurons in PD (Yasuda et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Time-dependent alterations in the rat nigrostriatal system after intrastriatal injection of fibrils formed by α–Syn and tau fragments

Yang

Wang²,

Zeng³

et al. 2022

Front. Aging Neurosci.

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IntroductionAccurate demonstration of phosphorylated α-synuclein aggregation and propagation, progressive nigrostriatal degeneration and motor deficits will help further research on elucidating the mechanisms of Parkinson’s Disease. α-synucleinN103 and tauN368, cleaved by activated asparagine endopeptidase in Parkinson’s Disease, robustly interacted with each other and triggered endogenous α-synuclein accumulation in a strong manner. However, the detailed pathophysiological process caused by the complex remains to be established.MethodsIn this study, rats were unilaterally inoculated with 15 or 30 μg of this complex or vehicle (phosphate buffered saline, PBS). Over a 6-month period post injection, we then investigated the abundance of pSyn inclusions, nigrostriatal degeneration, and changes in axonal transport proteins to identify the various dynamic pathological changes caused by pSyn aggregates in the nigrostriatal system.ResultsAs expected, rats displayed a dose-dependent increase in the amount of α-synuclein inclusions, and progressive dopaminergic neurodegeneration was observed throughout the study, reaching 30% at 6 months post injection. Impairments in anterograde axonal transport, followed by retrograde transport, were observed prior to neuron death, which was first discovered in the PFFs model.DiscussionThe current results demonstrate the value of a novel rat model of Parkinson’s disease characterized by widespread, “seed”-initiated endogenous α-Syn pathology, impaired axonal transport, and a neurodegenerative cascade in the nigrostriatal system. Notably, the present study is the first to examine alterations in axonal transport proteins in a PFF model, providing an appropriate foundation for future research regarding the mechanisms leading to subsequent neurodegeneration. As this model recapitulates some essential features of Parkinson’s disease, it provides an important platform for further research on specific pathogenic mechanisms and pre-clinical evaluations of novel therapeutic strategies.

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Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

Cited by 4 publications

References 70 publications

T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils

T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils

Meningeal T cells function in the central nervous system homeostasis and neurodegenerative diseases

Time-dependent alterations in the rat nigrostriatal system after intrastriatal injection of fibrils formed by α–Syn and tau fragments

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