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

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 neuroi...

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Bibliographic Details
Published in:Glia 2017-09, Vol.65 (9), p.1471-1490
Main Authors: Kim, Jae‐Hong, Ko, Pan‐Woo, Lee, Ho‐Won, Jeong, Ji‐Young, Lee, Maan‐Gee, Kim, Jong‐Heon, Lee, Won‐Ha, Yu, Ri, Oh, Won‐Jong, Suk, Kyoungho
Format: Article
Language:English
Subjects:
Activation
Amnesia
Animal models
Animals
Astrocytes
Astrocytes - metabolism
Astrocytes - pathology
Biomarkers - blood
Blood-brain barrier
Brain damage
Brain injury
Carotid arteries
Carotid artery
Cells, Cultured
Cerebral blood flow
chronic cerebral hypoperfusion
Cognition - physiology
Cognitive ability
Cognitive Dysfunction - metabolism
Cognitive Dysfunction - pathology
Death
Dementia
Dementia disorders
Dementia, Vascular - metabolism
Dementia, Vascular - pathology
Disease Models, Animal
Gliosis
global cerebral ischemia
Hippocampus
Hippocampus - blood supply
Hippocampus - metabolism
Hippocampus - pathology
Humans
Hypoxia-inducible factor 1a
Impairment
Inflammation
Ischemia
Lipocalin
Lipocalin-2 - administration & dosage
Lipocalin-2 - genetics
Lipocalin-2 - metabolism
Male
Membrane permeability
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia
Microglia - metabolism
Microglia - pathology
Microvessels - metabolism
Microvessels - pathology
Mortality
neuroinflammation
Neuronal-glial interactions
Neurons
Neurotoxicity
Occlusion
Patients
Permeability
Plasma levels
Recombinant Proteins - administration & dosage
Recombinant Proteins - metabolism
Rodents
Substantia alba
Vascular dementia
Vascular Endothelial Growth Factor A - metabolism
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Summary: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. Main Points Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
ISSN:0894-1491
1098-1136
DOI:10.1002/glia.23174