Blood-brain barrier disruption: a culprit of cognitive decline?

Abstract

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also from systemic diseases, which seriously influence the quality of life and life expectancy of patients. As a highly selective anatomical and functional interface between the brain and systemic circulation, the blood-brain barrier (BBB) plays a pivotal role in maintaining brain homeostasis and normal function. The pathogenesis underlying cognitive decline may vary, nevertheless, accumulating evidences support the role of BBB disruption as the most prevalent contributing factor. This may mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress and excitotoxicity. However, direct evidence showing that BBB disruption causes cognitive decline is scarce, and interestingly, manipulation of the BBB opening alone may exert beneficial or detrimental neurological effects. A broad overview of the present literature shows a close relationship between BBB disruption and cognitive decline, the risk factors of BBB disruption, as well as the cellular and molecular mechanisms underlying BBB disruption. Additionally, we discussed the possible causes leading to cognitive decline by BBB disruption and potential therapeutic strategies to prevent BBB disruption or enhance BBB repair. This review aims to foster more investigations on early diagnosis, effective therapeutics, and rapid restoration against BBB disruption, which would yield better cognitive outcomes in patients with dysregulated BBB function, although their causative relationship has not yet been completely established.

Keywords: Blood-brain barrier; Cognitive dysfunction; Molecular mechanism; Restoration; Risk factors.

Fig. 1

Schematic representation of the cellular and molecular structure of an intact BBB. The molecular and cellular components constitute an intact BBB which maintain brain homeostasis and function. The distribution of blood vessels and cells are shown on the left, a schematic cross-section of a blood vessel is shown in the center, and the molecular connections between endothelial cells are shown on the right. JAM: junctional adhesion molecule; PECAM: platelet endothelial cell adhesion molecule

Fig. 2

The risk factors attributing to BBB disruption

Fig. 3

The possible mechanisms underlying the BBB disruption. (a) Inflammatory factors can lead to down-regulation and degradation of TJs, mediated by VEGF and NO. MMPs, ROS and others can also induce a decrease in TJ protein expression. (b) A variety of factors including inflammation, ischemia and insulin resistance can lead to disintegration and death of ECs, leading to loss of ECs. Overexpression of endothelial adhesion molecules induces migration of leukocyte; activation of Adora2a decreases TJs expression; down-regulation of glucose transport proteins affects endothelial metabolism and inhibits LRP1 transcription, which disrupts the BBB integrity; and activation of TREM2 triggers endothelial oxidative stress. (c) Stress factors induce pericyte contraction and apoptosis, and hypoxia and inflammation trigger pericytes detachment from the basal lamina, leading to loss of pericytes. (d) Pathologic factors trigger astrocytes destruction and endfeet loss, and induce reactive astrocytes to secrete MMPs, proinflammatory cytokines, VEGF-A, ECGF1, and extracellular vesicles (EVs) containing inflammation-related proteins. (e) Activated microglia release proinflammatory factors, promote phagocytosis of astrocytic perivascular endfeet, and lower the expression of TJs. These mechanisms greatly impair molecular and cellular components and dysregulate cell-cell interaction, which underlie BBB disruption. BBB: blood brain barrier; TJs: tight junctions; ECs: endothelial cells; VEGF: vascular endothelial growth factor; ECGF1: endothelial cell growth factor 1; NO: nitrous oxide; MMPs: matrix metalloproteinases; ROS: reactive oxygen species; Adora2a: adenosine receptor 2a; LRP1: low-denisity lipoprotein receptor-related protein 1; TREM2: triggering receptor expressed on myeloid cells 2