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

The pathological hallmark of Parkinson's disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (alpha -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 alpha -syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human alpha -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.

Automated summary

The pathological hallmark of Parkinson's disease is the formation of Lewy bodies containing alpha-synuclein, but microvascular alterations have also been linked to neurodegeneration in PD. Using a human alpha-synuclein overexpression mouse model, researchers demonstrated compromised blood-brain barrier integrity, dynamic changes in vessel morphology, and activation of pericytes, supporting the occurrence of vascular pathology as an important aspect in PD. This model provides a powerful tool to investigate disease-modifying factors and guide the development of new treatments for Parkinson's disease.