Vascular Degeneration in Human Parkinson Disease: Novel Insights in the Pathologies, Functions and Mechanisms

Abstract

Degeneration of endothelial cells, a key component of cerebral capillaries, was reported in post-mortem brains of patients with Parkinson’s disease (PD). Using immunohistochemical staining and image analysis this study compared the changes of all structural components of the capillary, and their association with the blood-brain barrier (BBB) function, neuronal degeneration, PD specific pathological changes and biological process of vascular remodelling between the post-mortem brain tissues of human PD and age-matched control cases. While endothelial degeneration was profound the basement membrane (BM) is retained in PD brains, leading to an increase in string vessels formation in the middle frontal gyrus (MFG), caudate nucleus (CN) and substantia nigra (SN) of the PD cases. Glial fibrillary acid protein (GFAP) positive astrocyte was only increased in the CN of the PD cases where there was a leakage of the BBB. The biological process of vascular remodelling is impaired in the MFG by showing the loss of pericytes, reduced expressions of platelet-derived growth factor receptor-beta (PDGFRβ), vascular endothelial growth factor (VEGF) and proliferating vascular cells. There was no change in vascular-associated phosphorylated insulin-like growth factor (IGF-1Rp), but increased expression of IGF binding protein-2 (IGFBP-2) in the astrocytes in PD. The levels of IGF-1Rp in capillaries were correlated with the numbers of pericytes and proliferating cells in capillaries. In the MFG, the aggregation of α-synuclein and the autophagy marker p62 were both increased, but there was no change in activated microglia in PD brains. The loss of endothelium was associated with increased aggregation of α-synuclein. The study of co-changes using double labelled sections suggests the endothelial degeneration is more likely to be the co-pathology of α-synuclein aggregation and neuronal degeneration. In conclusion, the endothelial degeneration leads to the increased string vessel formation, which may contribute to hypoperfusion, but prevent BBB leakage and inflammation of PD brains. Impaired vascular remodelling and increased α-synuclein aggregation are associated with the endothelial degeneration in PD. Although the vascular degeneration is unlikely to be the primary cause of neuronal degeneration in PD, hypoperfusion may contribute to secondary neuronal degeneration.