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Alzheimer disease Related Functional Effects of the Urokinase-Type Plasminogen Activator (uPA) Gene PLAU


Alzheimer's disease (AD) is a complex neurodegenerative disorder that causes a progressive decline of cognitive abilities. Abundant evidence suggests that elevated amounts of the small highly amyloidogenic protein beta-amyloid (Aß) contributes to the neuro degenerative process in AD. Susceptibility loci for AD have been identified on chromosome 10q. Within the proximal region (~10q21-22), the plasminogen activator urokinase gene (PLAU) has been suggested as the strongest candidate due to its functional implication in plasmin generation, a serine protease capable of degrading Aß protein. Subsequent screening studies in multiple populations have identified an AD associated SNP within exon 6 of this gene (rs2227564).

This SNP has also been shown to be associated with elevated plasma Aß levels in 24 extended LOAD families and with elevated plaque counts in autopsy confirmed cases. PLAU knockout mice have also been shown to present with elevated plasma Aß levels. However, the functional relevance of the PLAU gene t o AD in particular to Aß levels in the brain and related neuropathology needs to be examined in greater detail. Through the generation of a PLAU knockout-APP23 mouse model, the use of sRNA inhibition (RNAi) in primary neuronal cell culture from APP23 mice and the use of other state of the art technologies we hope to improve the current understanding, and determine the functional relevance, of the PLAU gene in AD.

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