α2-Antiplasmin as a potential regulator of the spatial memory process and age-related cognitive decline

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.

Identification of Plasma Proteins as Biomarkers for Mild Cognitive Impairment and Alzheimer’s Disease Using Liquid Chromatography–Tandem Mass Spectrometry

“…Consequently, fibrin degrades and blood components can enter the brain, leading to inflammation and nerve cell damage. Studies using mouse models of AD have shown that suppression of A2AP expression increases plasmin activity, resulting in enhanced Aβ deposition and inflammation in the brain [37,38].…”

α2-Antiplasmin as a Potential Therapeutic Target for Systemic Sclerosis

“…In addition, profibrotic factors including CTGF, HMGB1 and IFN-γ induce α2AP production in fibroblasts [ 11 , 38 , 66 ], and the increase in α2AP expression may affect fibrosis progression in SSc. Furthermore, it has been reported that α2AP deficiency attenuates oxidative stress [ 117 ] and promotes apoptosis [ 17 ], and α2AP may affect the induction of oxidative stress and resistance to apoptosis in SSc. On the other hand, plasmin can activate MMPs, such as MMP-1, MMP-3, and MMP-9, and degrade ECM [ 118 , 119 , 120 ].…”

“…In addition, the α2AP neutralizing antibody enhances fibrinolysis and thrombus dissolution [ 23 , 25 , 147 ]. Furthermore, α2AP deficiency attenuates oxidative stress [ 117 ], and α2AP neutralization may attenuate oxidative stress in SSc.…”