Tau Exon 10 Inclusion by PrP^C through Downregulating GSK3β Activity

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Tau protein aggregation causes tauopathies, including Alzheimer's disease (AD).
• Tau mRNA alternative splicing, regulated by exon 10 inclusion/exclusion, determines 3R and 4R tau isoform balance.
• Cellular prion protein (PrP^C) modulates GSK3β activity, a key regulator of tau splicing.

Purpose of the Study:

• To investigate the role of PrP^C in regulating tau exon 10 alternative splicing.
• To elucidate the involvement of GSK3β in the PrP^C-mediated tau splicing mechanism.

Main Methods:

• Analysis of Alzheimer's disease human samples.
• Utilized mouse models with PrP^C ablation and tau overexpression.
• Functional studies using primary neuronal cultures.

Main Results:

• A parallel association was observed between PrP^C expression and tau 4R isoforms across all models.
• Reduction or ablation of PrP^C led to an increased tau 3R/4R isoform ratio.
• GSK3β activity was identified downstream of PrP^C in regulating tau splicing.

Conclusions:

• PrP^C plays a significant role in tau exon 10 inclusion.
• PrP^C exerts its influence on tau splicing through the inhibition of GSK3β activity.
• This mechanism highlights a novel pathway linking PrP^C to tauopathy pathogenesis.