Abstract
α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is also expressed in several parts of the brain, including the hippocampus and cerebral cortex. Our previous study demonstrated that α2AP knockout mice exhibit spatial memory impairment in comparison to wild-type mice, suggesting that α2AP is necessary for the fetal and/or neonatal development of the neural network for spatial memory. However, it is still unclear whether α2AP plays a role in the memory process. The present study demonstrated that adult hippocampal neurogenesis and remote spatial memory were enhanced by the injection of an anti-α2AP neutralizing antibody in WT mice, while the injection of α2AP reduced hippocampal neurogenesis and impaired remote spatial memory, suggesting that α2AP is a negative regulator in memory processing. The present study also found that the levels of α2AP in the brains of old mice were higher than those in young mice, and a negative correlation between the α2AP level and spatial working memory. In addition, aging-dependent brain oxidative stress and hippocampal inflammation were attenuated by α2AP deficiency. Thus, an age-related increase in α2AP might cause cognitive decline accompanied by brain oxidative stress and neuroinflammation. Taken together, our findings suggest that α2AP is a key regulator of the spatial memory process, and that it may represent a promising target to effectively regulate healthy brain aging.
Highlights
Α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is expressed in several parts of the brain, including the hippocampus and cerebral cortex
Enhancement of hippocampal neurogenesis and remote spatial memory by neutralization of α2AP To first determine whether α2AP mediates adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we examined the effect of a neutralizing antibody against α2AP on neurogenesis
As adult hippocampal neurogenesis is essential for long-term spatial memory [21, 26], we examined whether α2AP was involved in the remote spatial memory in an Morris water maze (MWM) test
Summary
Α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is expressed in several parts of the brain, including the hippocampus and cerebral cortex. Our previous study demonstrated that α2AP knockout mice exhibit spatial memory impairment in comparison to wild-type mice, suggesting that α2AP is necessary for the fetal and/or neonatal development of the neural network for spatial memory. It is still unclear whether α2AP plays a role in the memory process. We demonstrated that the α2AP−/−mice exhibit impaired memory, including working memory, spatial memory and fear conditioning memory, in comparison to WT mice [19] Considering these findings, α2AP is likely to be necessary for the fetal and neonatal development of the neural network for memory functions; it is still unclear whether α2AP plays a role in memory process
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