Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus

Abstract

In the present study, we investigated the effects of type 2 diabetes-induced hyperglycemia on the integrity of the blood–brain barrier and tight junction markers in the rat hippocampus. Forty-week-old diabetic (Zucker diabetic fatty, ZDF) rats and littermate control (Zucker lean control, ZLC) rats were used in this study. We evaluated the integrity of the blood–brain barrier by measuring sodium fluorescein extravasation and blood vessel ultrastructure. In addition, tight junction markers, such as zona occludens-1, occludin and claudin-5, were quantified by western blot analysis. ZDF rats showed significantly increased sodium fluorescein leakage in the hippocampus. Tight junction markers, such as occludin and claudin-5, were significantly decreased in the hippocampi of ZDF rats compared to those of ZLC rats. In addition, ZDF rats showed ultrastructural changes with phagocytic findings in the blood vessels. These results suggest that chronic untreated diabetes impairs the permeability of the hippocampal blood–brain barrier by down-regulating occludin and claudin-5, indicating that chronic untreated diabetes may cause hippocampus-dependent dysfunction.

Disruption of the hippocampal and hypothalamic blood–brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate

“…In regions of the brain where BBB integrity has been disrupted, such as the hippocampus, studies have shown that tight junction protein expression is decreased [29,30]. However, when regions not affected by HF diet consumption are examined, such as the parietal cortex, or at the whole brain level, the effect on tight junction expression is often absent [6,31].…”

“…Protein samples (250 ng) from the brains of CD-1 mice fed LF-and HF-diet with and without TPM treatment were blotted onto a nitrocellulose membrane with a slot blot apparatus. In the case of protein carbonyls, protein samples were derivatized by 2,4-dinitrophenylhydrazine (DNPH) to react with protein carbonyls to form protein hydrazones as previously described [29]. The membranes were incubated with rabbit polyclonal anti-DNPH antibody (1:100 dilution) to measure protein carbonyls, anti-nitrotyrosine antibody (1:200 dilution) and anti-4-hydroxynonenal polyclonal antibody (1:5000 dilution).…”

“…Endothelial cells are connected by specific tight junction proteins, such as claudins, occludins and Zona occludens (ZO-1, ZO-2, and ZO-3) and exhibit specific transport mechanisms and pinocytic vesicles. High-fat diet consumption decreases expression of tight junction proteins leading to reduced BBB integrity in parts of the brain affected by the diet such as the hippocampus, but not the parietal cortex or in the whole brain [6,[29][30][31]. In addition, decreased tight junction expression has been observed in STZ-induced diabetic mice and the leptinreceptor deficient db/db mice [12,32].…”

Differentiation of Urine-Derived Induced Pluripotent Stem Cells to Neuron, Astrocyte and Microvascular Endothelial Cells from a Diabetic Patient

“…Substantial evidence have observed that there were dramatic pathological neuronal changes in streptozotocin (STZ) diabetes rats/mice, including neuronal apoptosis and synaptic alterations (Cai et al, 2018, Sadeghi et al, 2016, reduced expression levels of glial cell line-derived neurotrophic factor (GDNF) which was discovered as a survival neurotrophic factor to potently promotes the survival of many types of neurons (Sadeghi et al, 2016), increased expression of astrocyte glial fibrillary acidic protein (GFAP) (Sadeghi et al, 2016, Baydas et al, 2003 . Moreover, diabetes and continuous high blood glucose could directly induce a vast spectrum of injuries of endothelial cells in cerebral vascular system (Xu et al, 2016), damage the permeability of BBB by downregulating the expression of occluding and claudin-5 (Yoo et al, 2016). Therefore, here we successfully created hiPSC-derived neuron (N), astrocyte (A) and microvascular endothelial cell (E), which displayed typical morphological characteristics and can be used to reveal the pathogenesis on molecular level and explore the innovative treatment strategies based on drug screening or other methods to target diabetic brain injury.…”

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

“…Brain tissue is characterized by the absence of TJ proteins including ZO-1, occludin, JAM-1, and claudin-5, paralleling edema. Chronic DM type 2 led to increased permeability of BBB and diminished expression of TJs (occludin, claudin-5) in hippocampus in rats (Yoo et al, 2016a). It has been shown recently that hippocampal BBB permeability in rats increased when these animals were fed a high fat/high sugar diet provided that they gained weight vs. ones did not gain weight (Davidson et al, 2012).…”