Relationship Between Amyloid-β Deposition and Blood-Brain Barrier Dysfunction in Alzheimer's Disease

Abstract

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer's disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood-brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

Keywords: Alzheimer’s disease; P-glycoprotein; amyloid-β; blood–brain barrier; low-density lipoprotein receptor-related protein 1; receptor for advanced glycation end products.

FIGURE 1

Vicious circle formed by BBB dysfunction and Aβ deposition. The dysfunction of BBB promotes the production of Aβ by activating β-secretase and γ-secretase. Meanwhile, BBB dysfunction also impairs the normal transport of Aβ, and leads to the abnormal accumulation of Aβ. The normal transport of Aβ through BBB depends on a variety of transporters on BBB, such as LRP1, RAGE and P-gp. During the development of AD, these transporters have abnormal expression and function, which causes abnormal Aβ transport and deposition, thereby leading to BBB destruction. The pathological factors involved in this procedure include MMPs, ROS, NF-κB, and Ca2 + -CaN. AD, Alzheimer’s disease; Aβ, Amyloid-β; BBB, Blood–brain barrier; CaN, Calcineurin; RAGE, receptor for advanced glycation end products; LRP1, low-density lipoprotein receptor-related protein 1; MMPs, Metalloproteinases; NF-κB, Nuclear factor-κB; P-gp, P-glycoprotein; ROS, reactive oxygen species.

FIGURE 2

The components of blood–brain barrier and its manifestations in different states. The BBB composed of astrocytes, pericytes and BMEC is an indispensable structure that mediates the material exchange between blood and brain. TJs, the highly specialized intercellular adhesion complex, acts as a selective barrier to regulate the transport of non-ionic molecules between blood and brain. BBB contributes to maintaining a stable microenvironment in the brain and normal function of neurons. In Alzheimer’s disease, cytotoxic Aβ destroys BMEC and TJs associated proteins, which suggests the destruction of the TJ system and the loss of BBB integrity. Aβ, Amyloid-β; BBB, Blood–brain barrier; TJs, Tight junctions; BMEC, brain microvascular endothelial cells.

FIGURE 3

The material exchanges between perivascular space, ISF and CSF. The perivascular space is a normal anatomical structure in the nervous system, which has important physical and immune functions. Continuous brain ISF enters into CSF through perivascular space (Virchow-Robin spaces, VRS), and drains into the blood through lymphatic vessels. This is one of the pathways to clear Aβ from the brain. Aβ, Amyloid-β; ISF, interstitial fluid; CSF, cerebrospinal fluid.

FIGURE 4

The production and clearance of Aβ in the brain. The red arrow represents the source of Aβ in the brain, and the blue arrow represents the ways of Aβ clearance. Different type of cells in the brain take part in the production of Aβ, including astrocytes, neurons and endothelial cells. In addition, Aβ in peripheral blood enters into the brain through RAGE, a transporter on BBB. There are a variety of Aβ clearance ways. (1) Aβ enters into peripheral blood through LRP1 transporter on BBB; (2) Aβ enters into CSF through perivascular space; (3) Aβ is degraded by Aβ proteolytic enzymes. Aβ, Amyloid-β; BBB, Blood–brain barrier; LRP1, low-density lipoprotein receptor-related protein 1; RAGE, receptor for advanced glycation end products.

FIGURE 5

The three-step mechanism of LRP1 regulating the clearance of Aβ. Firstly, LRP1 expressed on the endothelial cells of BBB, promotes the transportation of Aβ from the brain to blood circulation. Then, sLRP1 in peripheral blood binds to free Aβ, which prevents Aβ from flowing into the brain and contributes to the continuous clearance of Aβ. Finally, LRP1 in hepatocytes promotes the clearance of circulating Aβ. Meanwhile, the sLRP1-Aβ complexes and free Aβ are also cleared by kidney. Aβ, Amyloid-β; LRP1, low-density lipoprotein receptor-related protein 1; sLRP1, soluble low-density lipoprotein receptor-related protein 1.