Bactericidal/Permeability-Increasing Protein Improves Cognitive Impairment in Diabetic Mice via Blockade of the LPS-LBP-TLR4 Signaling Pathway.

Qin Sun,Tingxin Li,Yamei Li,Lingling Wei,Min Zhang,Shaoping Deng

doi:10.3389/fphys.2020.00718

Abstract

Emerging evidence suggests that the bactericidal/permeability-increasing protein (BPI) is involved in the process of cognitive impairment in diabetes. However, its underlying mechanism remains elusive. In this study, we found that BPI affects cognitive impairment due to diabetes through the lipopolysaccharide (LPS)-lipopolysacharide-binding protein (LBP)-toll-like receptor 4 (TLR4) signaling pathway. We examined the expression of BPI, LPS, LBP, CD14, and TLR4 in established mouse models of diabetes induced by high-fat diet (HFD) in combination with streptozotocin (STZ). Diabetic mice were then injected with adeno-associated-virus carrying BPI overexpression vectors and LPS. Fasting blood glucose, plasma insulin, and serum levels of inflammatory factors were examined. Then, glucose tolerance and, insulin resistance tests were used to measure systemic insulin sensitivity. Next, hippocampal tissue injury and cell apoptosis were examined by hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Diabetic mice displayed increased LPS expression and activation of the LPS-CD14-TLR4 signaling pathway. HFD mice following LPS treatment showed significantly increased serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and expressions of Bcl-2-associated X protein (Bax) and Aβ but decreased expression of Bcl-2 in hippocampal tissues, as well as enhanced fasting blood glucose, plasma insulin, glucose tolerance, insulin tolerance, cell apoptosis, aggravated hippocampal tissue injury and, ultimately, cognitive impairment. However, overexpression of BPI was able to rescue the aforementioned phenotypes driven by LPS treatment. Taken together, BPI could potentially provide relief from cognitive impairment in diabetic mice by disrupting the LPS-LBP-TLR4 signaling pathway, underscoring a possible alternative therapeutic strategy against the cognitive impairment associated with diabetes.

Highlights

Diabetes remains one of the most concerning public health concerns of the twenty-first century in developing countries, due in large part to the lack of accurate monitoring and surveillance (Zimmet et al, 2016)
The blood glucose level of the mice was measured and the results showed that the blood glucose level of high-fat diet (HFD) mice was significantly higher than that of the normal diet (ND)-fed mice (Figure 1A)
The levels of LPS and lipopolysacharide-binding protein (LBP) in the blood and, the expression of cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) signaling pathwayrelated factors were examined in mouse hippocampal tissues

Summary

Introduction

Diabetes remains one of the most concerning public health concerns of the twenty-first century in developing countries, due in large part to the lack of accurate monitoring and surveillance (Zimmet et al, 2016). Untimely deaths, medical complications and, financial burdens are on the rise due to the prevalence of undiagnosed diabetes, lack of education about this disease and, insufficient clinical practice standards (Koley et al, 2016). Patients with diabetes display a decline in cognitive function, especially with regards to memory, executive functions, and psychomotor efficiency while having an elevated risk of vascular dementia and Alzheimer’s disease (Pasquier, 2010; Biessels and Despa, 2018). Better understanding of the relationship between diabetes and cognitive impairment can help improve our management of symptoms and lead to more effective treatment for diabetic patients (Koekkoek et al, 2015)

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Results

Conclusion