Session Title: Neurodevelopment and Neurodegeneration
OVEREXPRESSION OF HUMAN PUROMYCIN-SENSITIVE AMINOPEPTIDASE (PSA) ATTENUATES ACCUMULATION OF PHOSPHORYLATED TAU
L. Kudo1, N. Vi2, K. Lau1, L. Parfenova1, M. Hui3, M. Gray4, X.W. Yang4, M. Wiedau-Pazos1, K.-S. Hui3, S. Karsten1
We previously demonstrated that puromycin-sensitive aminopeptidase (PSA) is a novel neuroprotective factor that prevents tau-induced neurodegeneration through its direct proteolytic function (Neuron, 2006, 51:549). To examine the effects of PSA overexpression on the progress of tau-induced neurodegeneration in vivo in the mammalian system, we generated multiple independent lines of PSA transgenic mice using bacterial artificial chromosome mediated technology. PSA transgenic mice are born normal, breed normally and do not reveal any gross anatomical or behavioral abnormalities. Based on Western- and Southern-blot analyses, we expanded three PSA founder lines. Characterization of these mice at 10 weeks, 4 months, 6 months, and 9 months have been conducted using Western blots and immunohistochemistry. Expression and activity of PSA as demonstrated by the enzyme activity assays were elevated in the brain of hemizygous PSA mice with highest PSA enzyme activity in the cortex (∼2.6 fold; p< 0.001) and cerebellum (∼2.4 fold; p< 0.05) followed by the brain stem (∼1.6 fold; p< 0.01). In addition, PSA was consistently elevated in muscle (∼1.9 fold; p< 0.01), kidney (∼1.9 fold; p< 0.05) and liver (∼2.1 fold; p< 0.01). PSA mice showed significantly reduced levels of endogenous phosphorylated Tau as compared to corresponding nontransgenic controls. To further investigate the effect of PSA on TAU-induced neurodegeneration, we have crossed our mice with TAU-P301L mice to generate double transgenic animals (TAU/PSA) expressing both the human PSA and the mutated TAU. TAU/PSA mice showed decrease in phosphorylated TAU compared to corresponding controls. Further analysis of PSA/TAU interaction is underway.