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

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Abstract

<p class="first" id="P1">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. </p>

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Most cited references 60

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Central nervous system pericytes in health and disease.

Ethan Winkler, Robert D Bell, Berislav Zlokovic (2011)

Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.

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Blood-brain barrier: structural components and function under physiologic and pathologic conditions.

Yuri Persidsky, Servio H. Ramirez, James Haorah … (2006)

The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream. The close interaction between BMVEC and other components of the neurovascular unit (astrocytes, pericytes, neurons, and basement membrane) ensures proper function of the central nervous system (CNS). Transport across the BBB is strictly limited through both physical (tight junctions) and metabolic barriers (enzymes, diverse transport systems). A functional polarity exists between the luminal and abluminal membrane surfaces of the BMVEC. As a result of restricted permeability, the BBB is a limiting factor for the delivery of therapeutic agents into the CNS. BBB breakdown or alterations in transport systems play an important role in the pathogenesis of many CNS diseases (HIV-1 encephalitis, Alzheimer's disease, ischemia, tumors, multiple sclerosis, and Parkinson's disease). Proinflammatory substances and specific disease-associated proteins often mediate such BBB dysfunction. Despite seemingly diverse underlying causes of BBB dysfunction, common intracellular pathways emerge for the regulation of the BBB structural and functional integrity. Better understanding of tight junction regulation and factors affecting transport systems will allow the development of therapeutics to improve the BBB function in health and disease.

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VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown.

Azeb Argaw, Blake Gurfein, Yueting Zhang … (2009)

Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.