Amyloid-β peptide alteration of tau exon-10 splicing via the GSK3β-SC35 pathway

Amyloid-beta peptide (A beta) and Tau protein are the lead constituents in the pathogenesis of Alzheimer's disease (AD). However, their inter-relationship in the disease process remains to be established. Tauopathy refers to a characteristic neurodegenerative process in AD. In tauopathy, Tau accumulates as a consequence of altered pre-mRNA splicing of tau exon 10, resulting in 3R (without exon 10)/4R (with exon 10) imbalance. We studied A beta effects on tau exon 10 pre-mRNA splicing and relevant signaling events. This is the first demonstration of A beta alteration of tau exon 10 splicing with an increase in 3R/4R ratio caused by reduced 4R expression. This A beta action is causally related to its activation of GSK-3 beta which in turn phosphorylates SC35, an enhancer in tau exon 10 splicing. The establishment of the A beta-GSK-3 beta-SC35 cascade broadens insight into development of novel strategies to modulate A beta action on tau exon 10 splicing for possible prevention of tauopathy. (c) 2010 Elsevier Inc. All rights reserved.