Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

Abstract

The blood-brain barrier (BBB) is a dynamic but solid shield in the cerebral microvascular system. It plays a pivotal role in maintaining central nervous system (CNS) homeostasis by regulating the exchange of materials between the circulation and the brain and protects the neural tissue from neurotoxic components as well as pathogens. Here, we discuss the development of the BBB in physiological conditions and then focus on the role of the BBB in cerebrovascular disease, including acute ischemic stroke and intracerebral hemorrhage, and neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Finally, we summarize recent advancements in the development of therapies targeting the BBB and outline future directions and outstanding questions in the field. We propose that BBB dysfunction not only results from, but is causal in the pathogenesis of neurological disorders; the BBB is more a contributor to the disruption of CNS homeostasis than a victim in neurological disorders.

Keywords: Alzheimer’s disease; Parkinson’s disease; acute ischemic stroke; blood-brain barrier; intracerebral hemorrhage; multiple sclerosis.

FIGURE 1

Endothelial cells, pericytes, the extracellular matrix, glial cells, and neurons are all basic components of the neurovascular unit. The blood-brain barrier (BBB) is composed of specialized endothelial cells. The transport system of the BBB includes carrier-mediated transport (CMT), receptor-mediated transport (RMT), efflux transporters, and ion transport. Gases, such as oxygen and carbon dioxide, and small lipophilic molecules less than 400 Da in size can freely diffuse across the BBB.

FIGURE 2

Schematic diagram of blood-brain barrier alterations in acute ischemic stroke. Reduced levels of glucose and oxygen result in dysfunction of EC ion transporters, inducing calcium overload and triggering inflammatory cascades. These inflammatory cascades further degrade tight junctions, thus aggravating brain edema and increasing infarct size.

FIGURE 3

Schematic diagram of blood-brain barrier changes in intracerebral hemorrhage. Perihematomal edema secondary to intracerebral hemorrhage can be divided into three phases. All the pathophysiological events result in degradation of tight-junction proteins, which exacerbate perihematomal edema and result in poor prognosis.

FIGURE 4

Genetic mutations and Aβ production in the blood-brain barrier increase the risk of AD. Genetic mutations, such as ABCA7, PICALM, and APOE, lead to dysfunction of BBB transport systems, resulting in Aβ deposition in the brain. Aβ accumulation gives rise to blood-brain barrier breakdown and cognitive impairment, characteristic of Alzheimer’s disease.