Hypoestoxide reduces neuroinflammation and α-synuclein accumulation in a mouse model of Parkinson’s disease

Kim, Changyoun; Ojo-Amaize, Emmanuel A.; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Desplats, Paula; Wrasidlo, Wolf; Adame, Anthony; Nchekwube, Emeka J.; Oyemade, Olusola A.; Okogun, Joseph I.; Chan, Michael D.; Cottam, Howard B.; Masliah, Eliezer

doi:10.1186/s12974-015-0455-9

Cited by 32 publications

(21 citation statements)

References 41 publications

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“…We have previously shown that in the α-syn tg there is an age-dependent neuronal loss in the hippocampus (Overk et al, 2014) accompanied by astrogliosis (Kim et al, 2015) and microgliosis (Watson et al, 2012). We chose to focus on these brain regions as we have previous shown that in addition to the vulnerability of the striato-nigral system, α-syn oligomers also accumulates in the CA3 neurons and promote selective degeneration mimicking DLB (Overk et al, 2014; Rockenstein et al, 2007; Rockenstein et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

El-Agnaf

Overk

Rockenstein

et al. 2017

Neurobiology of Disease

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Disorders with progressive accumulation of α-synuclein (α-syn) are a common cause of dementia and parkinsonism in the aging population. Accumulation and propagation of α-syn play a role in the pathogenesis of these disorders. Previous studies have shown that immunization with antibodies that recognize C-terminus of α-syn reduces the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy. These studies employed antibodies that recognize epitopes within monomeric and aggregated α-syn that were generated through active immunization or administered via passive immunization. However, it is possible that more specific effects might be achieved with antibodies recognizing selective species of the α-syn aggregates. In this respect we recently developed antibodies that differentially recognized various oligomers (Syn-O1, -O2, and -O4) and fibrilar (Syn-F1 and -F2) forms of α-syn. For this purpose wild-type α-syn transgenic (line 61) mice were immunized with these 5 different antibodies and neuropathologically and biochemically analyzed to determine which was most effective at reducing α-syn accumulation and related deficits. We found that Syn-O1, -O4 and -F1 antibodies were most effective at reducing accumulation of α-syn oligomers in multiple brain regions and at preventing neurodegeneration. Together this study supports the notion that selective antibodies against α-syn might be suitable for development new treatments for synucleinopathies such as PD and DLB.

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Section: Resultsmentioning

confidence: 99%

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

El-Agnaf

Overk

Rockenstein

et al. 2017

Neurobiology of Disease

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“…Antibody specificity for IL-1β was confirmed by preabsorption with recombinant mouse IL-1β, which blocked further staining with the IL-1β antibody. This antibody has been previously used for immunohistochemistry in mouse 38,39 and detects both the inactive, precursor and active form of IL-1β 40 . The Iba-1 antibody 41,42 and NeuN antibody 43,44 have been extensively used in mice.…”

Section: Methodsmentioning

confidence: 99%

IL-1β expression is increased and regulates GABA transmission following chronic ethanol in mouse central amygdala

Patel

Khom

Steinman

et al. 2019

Brain, Behavior, and Immunity

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The interleukin-1 system (IL-1) is a prominent pro-inflammatory pathway responsible for the initation and regulation of immune responses. Human genetic and preclinical studies suggest a critical role for IL-1β signaling in ethanol drinking and dependence, but little is known about the effects of chronic ethanol on the IL-1 system in addiction-related brain regions such as the central amygdala (CeA). In this study, we generated naïve, non-dependent (Non-Dep) and dependent (Dep) male mice using a paradigm of chronic-intermittent ethanol vapor exposure interspersed with two-bottle choice to examine 1) the expression of IL-1β, 2) the role of the IL-1 system on GABAergic transmission, and 3) the potential interaction with the acute effects of ethanol in the CeA. Immunohistochemistry with confocal microscopy was used to assess expression of IL-1β in microglia and neurons in the CeA, and whole-cell patch clamp recordings were obtained from CeA neurons to measure the effects of IL-1β (50 ng/ml) or the endogenous IL-1 receptor antagonist (IL-1ra; 100 ng/ml) on action potential-dependent spontaneous inhibitory postsynaptic currents (sIPSCs). Overall, we found that IL-1β expression is significantly increased in microglia and neurons of Dep compared to Non-Dep and naïve mice, IL-1β and IL-1ra bi-directionally modulate GABA transmission through both pre- and postsynaptic mechanisms in all three groups, and IL-1β and IL-1ra do not alter the facilitation of GABA release induced by acute ethanol. These data suggest that while ethanol dependence induces a neuroimmune response in the CeA, as indicated by increased IL-1β expression, this does not significantly alter the neuromodulatory role of IL-1β on synaptic transmission.

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“…After washing with PBS, sections were incubated with biotinylated-secondary antibodies (Vector Laboratories, Burlingame, CA) and subsequently signal was detected using ABC staining kit (Vector Laboratories). To determine microgliosis and striatal neurodegeneration, the optical density and percentage of Iba-1 positive area, numbers of NeuN-positive cells, and the striatal TH-optical density were analyzed using ImageJ (NIH) 44 .…”

Section: Methodsmentioning

confidence: 99%

Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril

Kim

Lee

et al. 2016

Sci Rep

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114

104

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A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate “strains” with distinct structures. Among the amyloidogenic proteins, α-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), α-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies.

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Hypoestoxide reduces neuroinflammation and α-synuclein accumulation in a mouse model of Parkinson’s disease

Cited by 32 publications

References 41 publications

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy

IL-1β expression is increased and regulates GABA transmission following chronic ethanol in mouse central amygdala

Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril

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