The plasminogen activating system in the pathogenesis of Alzheimer’s disease  

作　　者：Manuel Yepes 

机构地区：[1]Department of Neurology,Emory University School of Medicine,Atlanta,GA,USA [2]Department of Neurology,Veterans Affairs Medical Center,Atlanta,GA,USA [3]Division of Neuropharmacology and Neurologic Diseases,Yerkes National Primate Research Center,Atlanta,GA,USA

出　　处：《Neural Regeneration Research》2021年第10期1973-1977,共5页中国神经再生研究（英文版）

基　　金：This work was supported in part by National Institutes of Health Grant NS-NS091201(to MY)and VA MERIT Award IO1BX003441(to MY).

摘　　要：Dementia is a clinical syndrome that affects approximately 47 million people worldwide and is characterized by progressive and irreversible decline of cognitive,behavioral and sesorimotor functions.Alzheimer’s disease(AD)accounts for approximately 60–80%of all cases of dementia,and neuropathologically is characterized by extracellular deposits of insoluble amyloid-β(Aβ)and intracellular aggregates of hyperphosphorylated tau.Significantly,although for a long time it was believed that the extracellular accumulation of Aβwas the culprit of the symptoms observed in these patients,more recent studies have shown that cognitive decline in people suffering this disease is associated with soluble Aβ-induced synaptic dysfunction instead of the formation of insoluble Aβ-containing extracellular plaques.These observations are translationally relevant because soluble Aβ-induced synaptic dysfunction is an early event in AD that precedes neuronal death,and thus is amenable to therapeutic interventions to prevent cognitive decline before the progression to irreversible brain damage.The plasminogen activating(PA)system is an enzymatic cascade that triggers the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases:tissue-type plasminogen activator(tPA)and urokinase-type plasminogen activator(uPA).Experimental evidence reported over the last three decades has shown that tPA and uPA play a role in the pathogenesis of AD.However,these studies have focused on the ability of these plasminogen activators to trigger plasmin-induced cleavage of insoluble Aβ-containing extracellular plaques.In contrast,recent evidence indicates that activity-dependent release of uPA from the presynaptic terminal of cerebral cortical neurons protects the synapse from the deleterious effects of soluble Aβvia a mechanism that does not require plasmin generation or the cleavage of Aβfibrils.Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of dat

关 键 词：Alzheimer’s disease amyloid precursor protein amyloidβ NEUROSERPIN PLASMIN plasminogen activating system plasminogen activator inhibitor-1 synapse tissue-type plasminogen activator urokinase-type plasminogen activator 

分 类 号：R749.16[医药卫生—神经病学与精神病学]