The role of the PCTAIRE 3 kinase in Alzheimer's disease pathogenesis

Abstract

While over a decade has passed since the initial identification of PCTAIRE 3, relatively few studies have investigated the native substrates, regulatory factors or general function of the human protein. This manuscript is organized around four themes to elucidate the function of PCTAIRE 3 in the brain. First, the distribution of PCTAIRE 3 is investigated on a transcript level. Two transcripts encoding human PCTAIRE 3 were identified and the intron-exon structure of PCTAIRE 3 gene are reported. The next section addresses the generation of monoclonal antibodies to study PCTAIRE 3 on a protein level. Seven antibodies recognizing three different sites within a single immunodominant region of the N-terminal domain of human PCTAIRE 3 were characterized. The following chapter investigates the central hypothesis that PCTAIRE 3 is a modulator of tau protein phosphorylation in Alzheimer's disease. We report that PCTAIRE 3 is a PHF-associated kinase that is elevated in the temporal cortex of Alzheimer's disease brains and acts as an effector of tau phosphorylation. The final series of experiments investigate the endogenous function of PCTAIRE 3 in the brain by the characterization of a knockout mouse.;Elucidating which kinases are responsible for abnormal tau phosphorylation is an important aspect in understanding how Alzheimer's disease evolves. Moreover, since re-entry into the cell cycle is an early event in pathogenesis that precedes neurodegeneration, the identification of protein kinases such as PCTAIRE 3 may represent important new targets for combating the disease before brain cells become severely damaged.