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

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-beta (A beta) and intracellular aggregates of hyperphosphorylated tau. Significantly, although for a long time it was believed that the extracellular accumulation of A beta was 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 A beta-induced synaptic dysfunction instead of the formation of insoluble A beta-containing extracellular plaques. These observations are translationally relevant because soluble A beta-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 A beta-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 A beta via a mechanism that does not require plasmin generation or the cleavage of A beta fibrils. Below we discuss the role of the PA system in the pathogenesis of AD and the translational relevance of data published to this date.

Automated summary

Dementia is a global clinical syndrome, with Alzheimer's disease being the most common type. While it was previously believed that cognitive decline in dementia was caused by extracellular accumulation of A beta, recent studies have shown that it is actually associated with soluble A beta-induced synaptic dysfunction, which can be targeted for therapeutic interventions to prevent irreversible brain damage.