Urokinase-type Plasminogen Activator in the Ischemic Brain

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ABSTRACT Soluble Aβ-induced synaptic dysfunction causes progressive cognitive decline in Alzheimer’s disease (AD) patients. This is an early event that precedes neuronal death and thus is amenable to therapeutic interventions before the progression to irreversible brain damage. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) not only generates plasmin but also activates cell signaling pathways. Work funded by the active award supporting this Administrative Supplement application has revealed that uPA is abundantly found in synapses of excitatory neurons located in the II/III and V cortical layers of the mature murine, non-human primate and human brain, and that its release, triggered by synaptic activity, promotes the formation of synaptic contacts and the repair of synapses damaged by an ischemic injury. Activation of the Wnt-β-catenin pathway is crucial for synapse formation and preservation of synaptic structure and function. Soluble Aβ inhibits the Wnt-β-catenin pathway in the brain of AD patients, and the resultant impairment of β-catenin signaling causes synaptic dysfunction, amyloidogenic processing of the amyloid precursor protein (APP), tau phosphorylation and memory loss. In line with these observations, restoration of Wnt-β-catenin pathway function prevents soluble Aβ-induced synaptic dysfunction and cognitive decline. In this Administrative Supplement application we will use in vitro and in vivo experimental approaches to test the hypothesis that uPA protects the synapse from the harmful effects of soluble Aβ by its ability to activate the Wingless/Int1 (Wnt)-β-catenin pathway via a mechanism that does not require plasmin generation. Our hypothesis is within the scope of the active award, and supported by the following observations described in Preliminary Studies of this application: i) the abundance of uPA is significantly decreased in the synapse of AD patients; ii) uPA is an efficient activator of the Wnt-β-catenin pathway in cerebral cortical neurons by a mechanism that does not require plasmin generation; iii) uPA abrogates the inhibitory effect of soluble Aβ on the Wnt-β-catenin pathway; iv) uPA prevents Aβ-induced synaptic loss via Wnt-β-catenin pathway activation. And v) treatment with recombinant uPA (ruPA) protects the synapse from the harmful effects of soluble Aβ. Importantly, the relevance of uPA in the pathogenesis of AD is supported by findings that nucleotide polymorphisms of the uPA encoding gene are associated with late onset AD, and that the activity of uPA’s inhibitor [plasminogen activator inhibitor–1 (PAI-1)] is increased in the brain of AD patients. Thus, the hypothesis that will be tested in this Administrative Supplement application is novel and may lead to the discovery a new pathophysiological mechanism of AD and a potential therapeutic target to protect the synapse of AD patients.