Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes

Abstract

As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy.

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

“…As CAA progresses, the neurovascular unit degenerates in amyloid-laden vessels [ 40 , 53 ], affecting the integrity of the vessel wall and resulting in BBB leakage, vessel occlusion or rupture, leading to hemorrhage and decreased cerebral blood flow [ 2 ]. Also, under diabetic conditions, both the capillaries and larger vessels of the brain show a thickened basal lamina from collagen deposition, accumulated byproducts of lipid peroxidation, and deterioration of endothelial cells and pericytes [ 54 ].…”

“…In addition, oxidative stress has a key role in insulin resistance and progression of diabetes [ 73 , 74 ] and diabetic mice show vascular alterations associated with increased oxidative stress, pericyte dysfunction and cerebrovascular integrity compromise [ 75 ]. Likewise, advanced glycation end products, resulting from hyperglycemia in T2D, alter the structure and function of BBB proteins [ 62 ] and diabetes-induced inflammation leads to astrocytic feet swelling in small vessels, separation of the plasma membrane and accumulation of hypertrophic microglia [ 54 ].…”

Role of autophagy in angiogenic potential of vascular pericytes

“…Given the intricate and complex association of metabolic disorders with the vascular unit, it is postulated that a diabetic condition is likely to alter the function of cells in the BBB interface integrity ( Li et al, 2022 ). Lee and co-workers found that cellular components can affect the integrity of BBB via the interchange of metabolic byproducts ( Lee et al, 2022 ).…”

The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke

“…In MS, Wnt signaling dysfunction leads to blocked migration of NG2-glia along the vasculature, while NG2-glia accumulate around the vasculature, physically expelling astrocyte endfeet from the vascular surface, disrupting TJPs between endothelial cells, and increasing BBB permeability (Niu et al, 2019). Moreover, the proliferation of NG2-glia further exacerbates BBB injury in a diabetic model (Li et al, 2022a) and NG2-glia secrete matrix metalloproteinase 9 (MMP-9) to disrupt BBB integrity in the early stages of WM injury (Hu et al, 2022).…”