Blood-brain barrier dysfunction and Alzheimer's disease: associations, pathogenic mechanisms, and therapeutic potential

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ), hyperphosphorylation of tau, and neuroinflammation in the brain. The blood-brain barrier (BBB) limits solutes from circulating blood from entering the brain, which is essential for neuronal functioning. Focusing on BBB function is important for the early detection of AD and in-depth study of AD pathogenic mechanisms. However, the mechanism of BBB alteration in AD is still unclear, which hinders further research on therapeutics that target the BBB to delay the progression of AD. The exact timing of the vascular abnormalities in AD and the complex cause-and-effect relationships remain uncertain. Thus, it is necessary to summarize and emphasize this process. First, in this review, the current evidence for BBB dysfunction in AD is summarized. Then, the interrelationships and pathogenic mechanisms between BBB dysfunction and the risk factors for AD, such as Aβ, tau, neuroinflammation, apolipoprotein E (ApoE) genotype and aging, were analyzed. Finally, we discuss the current status and future directions of therapeutic AD strategies targeting the BBB. We hope that these summaries or reviews will allow readers to better understand the relationship between the BBB and AD.

Keywords: Alzheimer’s disease; aging; apolipoprotein E; blood-brain barrier; neuroinflammation.

Figure 1

BBB dysfunction accelerates Aβ deposition. Under physiological conditions, Aβ binds to LRP1, and peripheral clearance of Aβ occurs with the assistance of P-gp, which transports Aβ out of the brain across the BBB. Simultaneously, RAGE expressed by endothelial cells can bind to peripheral free Aβ to reuptake it into the brain. When LRP1 expression decreases and RAGE expression rises in the BBB, peripheral clearance of Aβ is blocked, and re-entry into the brain increases, which leads to Aβ accumulation in the brain. In addition, decreased GLUT1 expression in endothelial cells leads to BBB disruption and transcriptional repression of LRP1, which accelerates Aβ pathology and leads to secondary neurodegenerative changes, neuronal loss, and brain atrophy. Thus, the malignant accumulation of Aβ in the brain may become a destructive feedback loop that may eventually induce neuronal damage in the brain, leading to impaired cognitive and memory functions.

Figure 2

BBB dysfunction expedites tau formation and dispersal. Tau protein status determines the binding and stability of microtubule protein aggregates in neuronal cells. Hyperphosphorylation causes tau protein to lose its ability to bind microtubules, which triggers the formation of PHF and subsequently leads to the formation of NFTs. In addition, tau protein interacts with glial cells and leads to the release of proinflammatory cytokines, causing the dysfunction of TJ proteins, atrophy of pericytes, and disruption of basement membranes, which in turn exacerbates damage to the BBB. Eventually, the pathological effects of tau in the brain may spread to endothelial cells and pericytes, inducing and accelerating BBB dysfunction, which in turn leads to neuronal activity dysfunction.

Figure 3

The BBB is an important bridge between neuroinflammation and systemic inflammation. The main factors that disrupt the BBB and induce neurodegeneration are three inflammatory cytokines: IL-1β, TNF-α, and IL-6. In addition, inflammatory cytokines in the CNS can activate glial cells and alter their function, leading to microglial activation and further release of proinflammatory cytokines to breakdown TJ proteins, further disrupting the functional and structural integrity of the BBB. In turn, the early and progressive perivascular activation of glial cell aggregation triggered by BBB dysfunction contributes to neuronal damage in neuroinflammatory diseases.

Figure 4

ApoE4 contributes to increased susceptibility to BBB dysfunction. ApoE4 derived from astrocytes and pericytes leads to decreased LRP1 expression on pericytes, resulting in activation of the proinflammatory signal CypA/MMP9, which in turn disrupts the TJ between endothelial cells. Disruption of the BBB leads to neuronal uptake of multiple blood-derived neurotoxic proteins, as well as reduced microvascular and cerebral blood flow, which in turn causes secondary neuronal damage and cognitive decline.