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- Ekmark-Lewén, Sara, et al.
(författare)
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Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils
- 2023
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Ingår i: AGING BRAIN. - : Elsevier. - 2589-9589. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy against alpha-synuclein (alpha-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related alpha-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic alpha-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] alpha-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated alpha-syn (pS129 alpha-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target alpha-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other alpha-synucleinopathies.
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- von Euler Chelpin, Marianne, et al.
(författare)
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Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease
- 2020
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Ingår i: Journal of Parkinsons Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 10:4, s. 1429-1442
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Tidskriftsartikel (refereegranskat)abstract
- Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of alpha-synuclein protofibrils (alpha-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer's disease (AD, tau<350 pg/mL, amyloid-beta 42 (A beta(42))>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total alpha-synuclein (alpha-syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to alpha-syn PF, with no cross-reactivity to monomeric alpha-syn, or the beta- and gamma-synuclein variants. CSF la-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using alpha-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total la-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion: The developed method specifically quantifies alpha-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.
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