Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

Abstract

Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications.

Keywords: Blood brain barrier; Cognitive impairment; Diabetes; Endothelial cell; Neuroinflammation; Pericyte.

Figure 1

Structural adaptations of the BBB to prolonged hyperglycemia. (A) Components of the BBB under normal physiological conditions. The vessel lumen (red) is enclosed by endothelial cells (blue), which attenuate paracellular transport via TJs. A basement membrane (light green) encloses these components and encases pericytes (orange) associated with the vessel. Astrocytic end feet (green) surround the basement membrane, providing an additional barrier to brain parenchyma access (light blue). (B) Pathologic changes to the BBB following prolonged exposure to hyperglycemia. Capillary density is increased as a result of sprouting from existing microvasculature. The basement membrane exhibits thickening and barrier integrity is decreased, in part due to TJ alteration and increased paracellular diffusion. Lastly, pericytes associated with the vessel undergo degeneration, leading to ‘acellular capillary’ appearance histologically.

Figure 2

Impact of AGEs on cellular components of the BBB in vitro. Shimizu et al. (2013) demonstrated that AGEs may stimulate the production of fibronectin through RAGE and TGF-β, presumably leading to BM thickening. Additionally, claudin-5 expression is reduced in endothelial cells exposed to AGEs, which act through RAGE, VEGF, and MMP-2. Caudin-5 is also reduced by TGF-β exposure, suggesting that pericytes may modulate claudin-5 through this mediator (Shimizu et al., 2013). Given that VEGF, TGF-β, and MMP-2 are secreted proteins, it is assumed that VEGF and TGF-β act in an autocrine/paracrine manner while MMP-2 exerts its enzymatic action extracellularly.