Amyloid-β peptide alteration of tau exon-10 splicing via the GSK3β-SC35 pathway.
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.
Chen
Kun-Lin
KL
The Department of Medical Education and Research, Shih Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Yuan
Rey-Yue
RY
Hu
Chaur-Jong
CJ
Hsu
Chung Y
CY
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005091:Exons; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D012326:RNA Splicing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D016875:tau Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3