Abstract
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 model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-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.
Highlights
The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn)
In order to further validate that the overexpression of human α-syn-Green fluorescent protein (GFP) fusion protein in this model results in a progressive aggregation of α-syn-GFP, we measured soluble versus insoluble human α-syn by western blotting (Fig. 1c,d)
We examined pathological features of PD in a α-syn overexpression transgenic homozygote mice (TG) mouse model where human α-syn is overexpressed under the mouse α-syn promoter
Summary
The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Data is emerging that pericyte changes occur in certain neurological disorders and are associated with or even precede neuronal loss[12,13,14]. This is important as pericytes maintain the anatomical, biochemical and immune functions of the BBB, they regulate capillary flow, angiogenesis and the clearance of toxic products[15,16]. One of the responses of pericytes to pathology is their activation which is Disease Biomarker Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden. Characterized by expression of markers such as regulator of G-protein signaling 5 (RGS5) and neuron-glial antigen 2 (NG2)[17,18,19], and activation of pericytes has been observed in neurodegenerative d isorders[12,20]
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