Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer's Disease

Abstract

Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). While amyloid-β (Aβ) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist. Although further clinical studies should clarify whether BBB disruption is a specific feature of AD pathogenesis, increasing evidence indicates that each component of the neurovascular unit is significantly affected in the presence of AD-related pathologies in animal models and human patients. Conversely, since some portions of Aβ are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in exacerbated Aβ accumulation in the brain. Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Aβ accumulation and neurovascular unit impairments during disease progression.

Keywords: amyloid-β; astrocytes; basement membrane; cerebral amyloid angiopathy; endothelial cells; neurovascular unit; pericytes; tight junctions.

Figure 1

Blood-brain barrier (BBB) and the neurovascular unit. Pial arteries branch out into smaller arteries called penetrating arteries. The penetrating arteries go further down into the brain parenchyma, giving rise to parenchymal arterioles, which eventually branch off into capillaries. Whereas pial and penetrating arteries are covered by vascular smooth muscle cells and are separated from brain tissues by the parenchymal basement membrane (glia limitans), parenchymal arterioles and capillaries become associated with neurons and astrocytes. Parenchymal arterioles are covered by one layer of smooth muscle cells. In capillaries, endothelial cells form the BBB. BBB properties in endothelial cells are further maintained and regulated through communications with basement membranes and other neighboring cells in neurovascular unit such as pericytes, astrocytes, and interneurons. BBB indicates blood-brain barrier.

Figure 2

Physical and molecular properties of endothelial cells contributing to BBB integrity and function. Tight junction and adherens junction complexes between endothelial cells restrict paracellular flux across the BBB. In addition, some nutrients and essential molecules are selectively transported from luminal to abluminal membranes by specific influx transport systems. Most of the small lipophilic molecules passively diffused across the lipid bilayer are returned to the blood by ATP-dependent efflux transporters. ZO-1 (zonula occludens-1); JAM (junctional adhesion molecule); VE-cadherin (vascular endothelial-cadherin); lgG (immunoglobulin G).

Figure 3

Proposed model for BBB dysfunction in AD pathogenesis. Dysregulation of the neurovascular unit (e.g., diminished endothelial transport, loss of tight junction (TJ) integrity, basement membrane disorganization, pericyte degeneration, and astrocyte depolarization) is induced during Alzheimer’s disease (AD) progression, which is particularly associated with brain Aβ accumulation. These alterations, in turn, contribute directly or indirectly to the disturbed Aβ clearance in the neurovascular unit and across the BBB, thus setting up a vicious cycle in AD pathogenesis. In parallel, plasma protein leakage, reduced brain glucose uptake, and neuroinflammation caused by BBB damage may lead to further cellular toxicity, making neurons more susceptible to AD pathologies.