Blood-Brain Barrier Disruption Induced Cognitive Impairment Is Associated With Increase of Inflammatory Cytokine

Abstract

Patients with diabetes suffer the higher risk of dementia and the underlying pathological mechanism of cognitive dysfunction in diabetes is not fully understood. In this study, we explore whether the cognitive impairment in the diabetic rat is associated with increased blood brain barrier (BBB) permeability and the change of the inflammatory cytokine. Experimental diabetic rats were induced by single intraperitoneal injection of streptozotocin (STZ). Cognitive function was evaluated by Morris water maze in the normal and the diabetic rats, respectively. The spatial acquisition trials were conducted over five consecutive days and the probe test was performed on day 6, followed by working memory test on the next 4 days. Escape latency was recorded in the acquisition trials and working memory test; time spent in the target quadrant and the number of crossing the former platform were recorded in the probe test. BBB permeability was assessed by measuring the extravasation of IgG. The image of occludin and claudin-5 staining by a confocal microscope were acquired to measure the gap in the tight junction. Cytokines TNF-α, IL-1β and IL-6 mRNA expression were further examined by Real-time PCR. The time spent in the target quadrant within 30 s decreased in the 8-week STZ rats compared to that of the normal rats (p < 0.05), while no difference was seen in the performance of working memory between the diabetic and normal rats. IgG leakage significantly increased in the brain parenchyma of the 8-week STZ rats compared to the normal rats (p < 0.05). The immunostaining of occludin and claudin-5 suggested the gap in the tight junction increased in the 8-week STZ rats compared to the normal rats (p < 0.05). Moreover, TNF-α and IL-6 mRNA also increased in the brain of 8-week STZ rats compared to the normal rats (p < 0.05). These results suggested that loss of BBB integrity might contribute to progressive impairment of cognitive in the diabetic rats. The increase of TNF-α and IL-6 expression might trigger the disruption of BBB in the brain, which eventually caused cognitive impairment in the 8-week STZ rats.

Lipoprotein‐associated phospholipase A2: The story continues

“…In particular, the tight junctions between the brain vascular endothelial cells (BVECs), comprising occludin proteins, claudin proteins, and junctional adhesion molecules, are vital for the structural and functional integrity of BBB . Therefore, BBB breakdown, due to disruption of the tight junctions, inflammatory responses, or other risk factors, may enhance its permeability and induce the leakage of harmful substances from blood vessels into the brain, contributing to the process of AD . Very recently, Nation et al demonstrated that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus and established BBB breakdown as an early biomarker of human cognitive dysfunction in individuals with and without Aβ or phosphorylated tau (pTau) positivity.…”

“…176 Therefore, BBB breakdown, due to disruption of the tight junctions, inflammatory responses, or other risk factors, may enhance its permeability and induce the leakage of harmful substances from blood vessels into the brain, contributing to the process of AD. 175,177 Very recently, Nation et al 178 demonstrated that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus and established BBB breakdown as an early biomarker of human cognitive dysfunction in individuals with and without Aβ or phosphorylated tau (pTau) positivity. Therefore, the authors concluded that neurovascular dysfunction might be a previously underappreciated promotor of AD, independent of the classic pathophysiological hallmarks.…”

Patients with chronic autoimmune demyelinating polyneuropathies exhibit cognitive deficits which might be associated with CSF evidence of blood-brain barrier disturbance

“…Studies with other patient populations and disease models have also suggested a link between autoimmune-mediated BBBd and cognitive/neuropsychiatric deficits (and thus a CNS involvement) [7][8][9]. Findings from the field of rheumatoid arthritis (RA) show that CNS involvement in RA occurs possibly due to BBBd associated with chronic inflammation and that circulating immune complexes may cause neuroinflammatory responses in the brain [36].…”

“…Additionally, we compared the patients' performance in each neuropsychological test with a group of healthy controls (HC) after adjusting for confounding variables. Last but not least, since experimental and observational studies have suggested a link between autoimmune-mediated BBBd and cognitive deficits [7][8][9], we investigated the association between the integrity of the BBB (as measured by the cerebrospinal fluid (CSF)/serum albumin quotient determined during the time of first CAPD diagnosis) and current cognitive performance.…”

Lactobacillus plantarumTWK10‐fermented soymilk improves cognitive function in type 2 diabetic rats

“…18 Glucose levels were assessed for 3 weeks after STZ injection to ensure that diabetes was not reversed. In week 14, the diabetic rats were administered the WE and EE of TWK10-fermented soy milk for 6 weeks (weeks [14][15][16][17][18][19][20], and after performing the Morris water maze (MWM) test, the rats were fasted overnight and sacrificed. Blood and aortic and brain tissues were harvested.…”