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

Abstract

Amyloid-beta peptide (Aβ) 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 Aβ effects on tau exon 10 pre-mRNA splicing and relevant signaling events. This is the first demonstration of Aβ alteration of tau exon 10 splicing with an increase in 3R/4R ratio caused by reduced 4R expression. This Aβ action is causally related to its activation of GSK-3β which in turn phosphorylates SC35, an enhancer in tau exon 10 splicing. The establishment of the Aβ-GSK-3β-SC35 cascade broadens insight into development of novel strategies to modulate Aβ action on tau exon 10 splicing for possible prevention of tauopathy.

Keywords

• Aβ
• Alzheimer's disease
• GSK3β
• Tau exon 10 splicing
• SC35
• Tauopathy