The role of vasculature in the neurodegeneration in Parkinson's disease

Abstract

Parkinson's disease (PD) is an age-related, progressive and neurodegenerative disease characterised by movement disorders. The condition affects approximately 1% of the population over the age of 60 worldwide. The gold standard treatment for this disease is symptomatic and short-term. PD pathology exceeds the simple wiring diagrams used to describe the dopamine depletion and neuronal imbalance and there is no cure. PD has a strong neurodegenerative component. There is extensive information in neuronal cell death in Parkinson’s which is accompanied by the presence of Lewy bodies as well as extensive astrocyte activation and gliosis. Vascular degeneration has been identified as a key pathology in neurodegeneration of ageing and Alzheimer's disease (AD). However the evidence of degenerative features in surrounding blood vessels in PD is limited. In order to develop effective therapies for PD, a complete understanding of the neurodegenerative process must be attained. Thus, we postulated that as a neurodegenerative disease, Parkinson’s may have a vascular aspect in its pathology. Ten PD cases and six age-matched controls were used in immunohistochemical experiments aimed at characterising the vascular changes in PD. The endothelial cells in vessels were immunohistochemically visualised with the antibodies rabbit anti- factor VIII and mouse anti GFAP in 50μm fixed frozen human brain sections. Fluorescent IHC studies with VEGF Factor VIII antibodies were completed in order to determine the colocalisation of angiogenic factors in PD blood vessels. Our findings show a significant decrease in vascular density and average vessel length in the substantia nigra and middle frontal gyrus of the cortex of PD brains. Endothelial cells in PD blood vessels appeared to have Factor VIII+ cluster-like inclusions; this has never been reported in PD vascular studies. The number and area of these inclusions was significantly higher in PD than in the age-matched controls. The capillary network of PD cases appeared to be degraded and branching data and angiogenesis data have shown that the vascular remodelling process may be impaired. Damage to the vascular network appeared to be widespread and highly variable. It is unclear whether the vascular damage predates neuronal pathology or if it occurs in tandem, however it does appear as if every component of the glial neurovascular unit is compromised as part of the PD pathological process. This finding may bring us one step closer to understanding the pathological origins of what remains a largely unaddressed global disease.