Long-term polarization of microglia upon α-synuclein overexpression in nonhuman primates

Barkholt, Pernille; Sanchez-Guajardo, Vanesa; Kirik, Deniz; Romero‐Ramos, Marina

doi:10.1016/j.neuroscience.2012.02.004

Cited by 66 publications

(53 citation statements)

References 70 publications

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“…Other studies have compared human WT and mutant A53T α-synuclein encoded by viral vectors in other species. On the one hand, Eslamboli and colleagues reported that the A53T variant induces a significantly enhanced dopaminergic neuron loss when compared to WT at one year after rAAV nigral injection in non-human primate brain and, correlating with the degree of induced cell death, two different microglia activation profiles were reported [55,57]. On the other hand, other studies performed in rats and non-human primates showed that rAAV vector-based delivery of WT and A53T α-synuclein induces a comparable neurodegenerative process, as well as aggregate formation [23,29,56].…”

Section: Discussionmentioning

confidence: 99%

rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

Oliveras-Salvá

Perren

Casadei

et al. 2013

Mol Neurodegeneration

147

115

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BackgroundAlpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra.ResultsWe noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants.ConclusionsIn conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.

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Section: Discussionmentioning

confidence: 99%

rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

Oliveras-Salvá

Perren

Casadei

et al. 2013

Mol Neurodegeneration

147

115

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“…LPS induced a persistent microgliosis, production of inflammatory molecules, and a progressive degeneration of nigrostriatal neurons when administered to transgenic mice overexpressing human A53T mutant α-synuclein, but not in wild type α-synuclein mice, suggesting that microglia bridge neuroinflammation and α-synuclein-induced cellular damage in mediating chronic degeneration in PD (Gao et al, 2011a). Moreover, studies in α-synuclein overexpressing mice and primates have been pivotal to demonstrate that levels of α-synuclein-induced neuronal pathology, either in presence or absence of DA degeneration, strictly modulate the phenotype of activated microglia (Barkholt et al, 2012; Sanchez-Guajardo et al, 2010). …”

Section: Microgliosis In Models Of Pd-like Degenerationmentioning

confidence: 99%

“…Studies in rats and primates overexpressing viral vector driven human α-synuclein have provided convincing evidence that microglia acquire different phenotypes and display different effector functions at early versus late stages of neurodegeneration (Barkholt et al, 2012; Sanchez-Guajardo et al, 2010). In rats overexpressing viral driven human α-synuclein, microglia assumed different morphology and phenotype depending on the level of α-synuclein expression and the related degree of α-synuclein-induced DA degeneration (Sanchez-Guajardo et al, 2010).…”

Section: Microglia Activation States In Animal Models Of Pd-like Dmentioning

confidence: 99%

Microglial phenotypes in Parkinson’s disease and animal models of the disease

Joers

Tansey

Mulas

et al. 2017

Progress in Neurobiology

221

160

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Over the last decade the important concept has emerged that microglia, similar to other tissue macrophages, assume different phenotypes and serve several effector functions, generating the theory that activated microglia can be organized by their pro-inflammatory or anti-inflammatory and repairing functions. Importantly, microglia exist in a heterogenous population and their phenotypes are not permanently polarized into two categories; they exist along a continuum where they acquire different profiles based on their local environment. In Parkinson’s disease (PD), neuroinflammation and microglia activation are considered neuropathological hallmarks, however their precise role in relation to disease progression is not clear, yet represent a critical challenge in the search of disease-modifying strategies. This review will critically address current knowledge on the activation states of microglia as well as microglial phenotypes found in PD and in animal models of PD, focusing on the expression of surface molecules as well as pro-inflammatory and anti-inflammatory cytokine production during the disease process. While human studies have reported an elevation of both pro- or anti-inflammatory markers in the serum and CSF of PD patients, animal models have provided insights on dynamic changes of microglia phenotypes in relation to disease progression especially prior to the development of motor deficits. We also review recent evidence of malfunction at multiple steps of NFκB signaling that may have a causal interrelationship with pathological microglia activation in animal models of PD. Finally, we discuss the immune-modifying strategies that have been explored regarding mechanisms of chronic microglial activation.

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“…Howev-159 er, we believe the microglia response will differ as the dis-160 ease progresses, as they will respond to neuronal 161 changes such as alpha-synuclein modification, differ-162 ences in neurotransmitters release and neuronal death. 163 In fact, we have shown in an alpha-synuclein model of 164 PD both in rodents and primates, that the microglia 165 response is early, preceding cell death, but not static 166 (Sanchez-Guajardo et al, 2010;Barkholt et al, 2012). 167 Also in vitro microglia's response to alpha-synuclein is 168 complex, with both pro and anti-inflammatory profiles 169 co-existing in parallel (Reynolds et al, 2008b to apoptosis (Veenman and Gavish, 2012), increased pro-188 liferation and phagocytosis (Choi et al, 2011) and its 189 modulation seems to be indeed involved in microglia acti-190 vation (Veiga et al, 2007).…”

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confidence: 99%

The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments

2015

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Long-term polarization of microglia upon α-synuclein overexpression in nonhuman primates

Cited by 66 publications

References 70 publications

rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

Microglial phenotypes in Parkinson’s disease and animal models of the disease

The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments

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