GSK3β is suggested to be a key enzyme for the development of AD. This kinase phosphorylates β-catenin and then labels it for subsequent ubiquitylation and degradation in proteasome 26S. It also indirectly affects stability of β-catenin by presenilin phosphorylation. Inhibition of the GSK3β is known to stabilize β-catenin and induce its translocation to nuclei. Our data show that cytoplasmic/nuclear β-catenin is specifi cally expressed in thalamic neurons in the adult mouse forebrain (1,2). We have performed an in silico screening for β-catenin neuronal targets and identifi ed 432 putative Lef1/β-catenin genes. Among them there are those encoding 23 proteins involved in cell adhesion, 12 voltage-gated ion channels, 10 proteins involved in synaptic vesicle organization and transport, and 13 neurotransmitter receptors. Using low density custom arrays with putative genes we established potential β-catenin targets in post-mitotic neurons. We plan to fi nd out which gene promoters are sensitive to β-catenin in neurons and to check, which drugs that inhibit GSK3β, affect the expression of β-catenin dependent gene targets. This might identify the downstream target(s) of the GSK3β pathways in neurons as potential sites for novel AD drugs with higher specifi city than the inhibitors of GSK3β. 1. Misztal et al. 2007, Acta Neurobiol Exp 67(3): 293, abstract; 2. Wisniewska et al. 2007, Acta Neurobiol Exp 2007, 67(3): 306.
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