Dataset Information

Human ?-synuclein overexpression in a mouse model of Parkinson's disease leads to vascular pathology, blood brain barrier leakage and pericyte activation.

ABSTRACT: The pathological hallmark of Parkinson's disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (?-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human ?-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human ?-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood-brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.

SUBMITTER: Elabi O

PROVIDER: S-EPMC7806665 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human α-synuclein overexpression in a mouse model of Parkinson's disease leads to vascular pathology, blood brain barrier leakage and pericyte activation.

Elabi Osama O Gaceb Abderahim A Carlsson Robert R Padel Thomas T Soylu-Kucharz Rana R Cortijo Irene I Li Wen W Li Jia-Yi JY Paul Gesine G

Scientific reports 20210113 1

The pathological hallmark of Parkinson's disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse ...[more]

PMID: 33441868

Similar Datasets

Project description:BackgroundChronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood-brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored.MethodsIn this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA.ResultsWe noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation.ConclusionsOur results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.

Dataset Information

Human ?-synuclein overexpression in a mouse model of Parkinson's disease leads to vascular pathology, blood brain barrier leakage and pericyte activation.

Publications

Human α-synuclein overexpression in a mouse model of Parkinson's disease leads to vascular pathology, blood brain barrier leakage and pericyte activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets