Role of Hippocampal Lipocalin-2 in Experimental Diabetic Encephalopathy

Abstract

Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system (CNS) that is characterized by degenerative neurochemical and structural changes leading to impaired cognitive function. While the exact pathophysiology of diabetic encephalopathy is not well-understood, it is likely that neuroinflammation is one of the key pathogenic mechanisms that cause this complication. Lipocalin-2 (LCN2) is an acute phase protein known to promote neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes, thereby inducing proinflammatory mediators in a range of neurological disorders. In this study, we investigated the role of LCN2 in multiple aspects of diabetic encephalopathy in mouse models of diabetes. Here, we show that induction of diabetes increased the expression of both Lcn2 mRNA and protein in the hippocampus. Genetic deficiency of Lcn2 significantly reduced gliosis, recruitment of macrophages, and production of inflammatory cytokines in the diabetic mice. Further, diabetes-induced hippocampal toxicity and cognitive decline were both lower in Lcn2 knockout mice than in the wild-type animals. Taken together, our findings highlight the critical role of LCN2 in the pathogenesis of diabetic encephalopathy.

Lipocalin‐2: Its perspectives in brain pathology and possible roles in cognition

“…Several studies have shown no significant difference between the cognitive function of wild‐type mice and LCN2 null mice (Table ) . These findings suggest that LCN2 may not have a role in the cognitive process under normal physiological conditions.…”

“…Under physiological conditions in a murine model, the expression of LCN2 mRNA and LCN2 protein in the brain appears to be very low to absent . However, only a few studies have reported LCN2 protein expression in the hippocampus, cortex and amygdala of normal mice and the hippocampus of normal adult rats …”

“…Table lists studies conducted in a rodent model that assessed the effect of LCN2 on cognitive function under pathological conditions. The cognitive dysfunction from various pathological conditions is associated with increased LCN2 levels in plasma . Those pathological conditions included global brain ischaemia, chronic hypoperfusion, the diabetic brain and obese mice .…”

“…The cognitive dysfunction from various pathological conditions is associated with increased LCN2 levels in plasma . Those pathological conditions included global brain ischaemia, chronic hypoperfusion, the diabetic brain and obese mice . The studies showed that cognition (focusing on spatial and hippocampal‐dependent memories) was negatively correlated with plasma LCN2 levels .…”

“…Although previous studies have shown that LCN2 is undetectable in the brain under physiological conditions, other studies showed that LCN2 is expressed only in specific brain regions . In addition, the up‐regulation of brain LCN2 expression has been found to occur in response to injury and inflammation and it has been suggested that LCN2 could modulate cognitive function in Alzheimer's disease (AD) .…”