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.