Astrocytic VEGFA: An essential mediator in blood–brain‐barrier disruption in Parkinson's disease

Abstract

The integrity of blood–brain‐barrier (BBB) is essential for normal brain functions, synaptic remodeling, and angiogenesis. BBB disruption is a common pathology during Parkinson's disease (PD), and has been hypothesized to contribute to the progression of PD. However, the molecular mechanism of BBB disruption in PD needs further investigation. Here, A53T PD mouse and a 3‐cell type in vitro BBB model were used to study the roles of α‐synuclein (α‐syn) in BBB disruption with the key results confirmed in the brains of PD patients obtained at autopsy. The A53T PD mouse studies showed that the expression of tight junction‐related proteins decreased, along with increased vascular permeability and accumulation of oligomeric α‐syn in activated astrocytes in the brain. The in vitro BBB model studies demonstrated that treatment with oligomeric α‐syn, but not monomeric or fibrillar α‐syn, resulted in significant disruption of BBB integrity. This process involved the expression and release of vascular endothelial growth factor A (VEGFA) and nitric oxide (NO) from oligomeric α‐syn treated astrocytes. Increased levels of VEGFA and iNOS were also observed in the brain of PD patients. Blocking the VEGFA signaling pathway in the in vitro BBB model effectively protected the barrier against the harmful effects of oligomeric α‐syn. Finally, the protective effects on BBB integrity associated with inhibition of VEGFA signaling pathway was also confirmed in PD mice. Taken together, our study concluded that oligomeric α‐syn is critically involved in PD‐associated BBB disruption, in a process that is mediated by astrocyte‐derived VEGFA.

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

“…In post-mortem brain tissues of patients with Parkinson’s disease, elevated VEGF-A and nitric oxide levels were detected at sites of astrocytic alpha-synuclein deposition. 22 Inhibition of VEGF-A blocked the deleterious effects of VEGF-A on the blood-brain barrier in a mouse model of Parkinson’s disease, especially among younger mice, suggesting more beneficial effects early in disease pathogenesis.…”

Microvascular Changes in Parkinson’s Disease- Focus on the Neurovascular Unit

“…Findings indicating angiogenesis in PD are supported by reports showing an upregulation of the pro-angiogenic molecule Vascular Endothelial Growth Factor (VEGF) in the SNpc of PD patients ( Wada et al, 2006 ; Yasuda et al, 2007 ; Lan et al, 2021 ) and non-human primates ( Barcia et al, 2005 ). Increased levels of soluble VEGF receptor-2 and placental growth factor, and lower levels of angiopoietin 2 (an anti-angiogenic molecule) were detected in the CSF of PD patients ( Janelidze et al, 2015 ).…”

“…A study using the A53T PD mouse model showed that the expression of tight junction-related proteins at the BBB decreased leading to increased vascular permeability ( Lan et al, 2021 ). When we examined the temporal dynamics of BBB leakage in another progressive α-syn-PD mouse model ( Elabi O. et al, 2021 ), we detected significant extravascular fibrinogen accumulation already at the early stage preceding behavioral deficits ( Elabi O. et al, 2021 ).…”

Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model

“…Alternatively, the antibodies might recognize different aSyn cleavage products, conformations or aggregation forms such as oligomers of different sizes, protofibrils and fibrils. Indeed, oligomeric aSyn has been observed in reactive astrocytes in the A53T PD mouse model and related to blood–brain-barrier disruption [ 81 ]. Also in human PD brain, aSyn-immunoreactive astrocytes have been observed [ 82 , 83 ].…”