Astrocyte‐derived lipocalin‐2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia

Abstract

Lipocalin-2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post-tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2-deficient mice, compared with wild-type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood-brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1-neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF-1α-LCN2-VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.

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 …”

“…LCN2 itself could be harmful to brain cells, particularly to neurones via both direct and indirect effects. Regarding the direct effect, LCN2 itself increased the susceptibility of neurones to toxic stimuli . In the case of the indirect effect, LCN2 could increase glial activity, leading to an increase in inflammatory processes .…”

“…The expression of 24p3R has been reported in the choroid plexus, neurones and astrocytes . However, it has been found primarily in the hippocampus . Another receptor called megalin, or LRP‐2, is a low‐density lipoprotein with multi‐ligand binding sites located in the ependymal cells in the ventricular wall of the brain, endothelial cells and choroid plexus .…”

“…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) .…”