Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease

Abstract

The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

Keywords: BBB; Parkinson disease; astrocytes; endothelial cells; reactive astrogliosis.

Figure 1

BBB disruption in PD. During PD development, increased ROS production leads to the accumulation of α-synuclein in DAneurons, and this is accompanied by mitochondrial dysfunction and increased neuronal death. Concurrently, astrocyte and microglia became activated, promoting cytokine release, which in turn affects endothelial tight junctions, pericyte phenotype and BBB permeability.

Figure 2

Protective strategies of astrocytes during BBB disruption. In advanced stages of PD, BBB disruption takes place and causes a lost in barrier permeability, entrance of toxic substances and in some instances immune cell infiltration. Processes such as increased ROS production, reactive gliosis and cellular death will inevitably occur. Astrocytic response to BBB disruption includes the production of antioxidative molecules like GSH and ascorbate, generation of growth factors like Brain derived neurotrophic factor (BDNF) and GDNF that could alleviate the cellular death and promote angiogenesis. Furthermore, astrocytes are important in the genetic regulation of endothelial proteins from the tight junction like Occludin and ZO-1. During chronic brain damage, astrocytes also induce the liberation of cytokines like TNF-α, IL-1B, IL-6, important in microglial activation and neuronal death.