Neurovascular Unit Dysfunction and Neurodegenerative Disorders

Abstract

The neurovascular unit (NVU), composed of vascular cells, glial cells, and neurons, is the minimal functional unit of the brain. The NVU maintains integrity of the blood-brain barrier (BBB) and regulates supply of the cerebral blood flow (CBF), both of which are keys to maintaining normal brain function. BBB dysfunction and a decreased CBF are early pathophysiological changes in neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In this review, we primarily focus on the NVU in AD as much research has been performed on the connection between NVU dysfunction and AD. We also discuss the role of NVU dysfunction in the pathophysiological mechanisms of PD and ALS. As most neurodegenerative diseases are difficult to treat, we discuss several potential drug targets that focus on the NVU that may inform novel vascular-targeted therapies for AD, PD, and ALS.

Keywords: Alzheimer’s disease; blood–brain barrier; neurodegenerative disease; neurovascular unit; target.

FIGURE 1

Structural diagram of the neurovascular unit (NVU) and the composition of tight junctions and adherens junctions. The NVU is composed of vascular cells (including endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes, microglia, and oligodendroglia), and neurons. Pericytes and astrocyte end-feet surround endothelial tubes. Adjacent endothelial cells are connected by tight junctions and adherens junctions. The tight junction is mainly composed of claudin, occludin, and junctional adhesion molecules, whereas the adherens junction is composed of vascular endothelial (VE) cadherin. NVU, neurovascular unit.

FIGURE 2

Clearance of β-amyloid (Aβ) from the brain is impaired through several mechanisms. (1) Decreased expression of LRP1 on endothelial cells causes decreased transport of Aβ from the brain to the peripheral circulatory system. (2) P-gp is an ATP-dependent efflux transporter that is expressed in the luminal surface of endothelial cells. Deficient expression of P-gp decreases Aβ clearance. (3) RAGE is an immunoglobulin superfamily member and a receptor for Aβ. Increased expression of RAGE in endothelial cells leads to more influx of Aβ from the peripheral circulatory system to brain parenchyma. (4) Tight junction proteins such as occludin, claudins, and ZO-1 are reduced in endothelial cells, thereby leading to impairment of BBB integrity. Apart from disruption of the BBB, decreased CBF leads to hypoxia, which upregulates the production of β- and γ-secretase. Increased β- and γ-secretase increases the cleavage of Aβ from APP. LRP1, low-density lipoprotein receptor-related protein 1; P-gp, P-glycoprotein; RAGE, receptor for advanced glycation end products; ZO-1, zonula occludens-1; BBB, blood–brain barrier; CBF, cerebral blood flow; APP, amyloid precursor protein.