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Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model
Kathleen M Schoch1, Sarah L DeVos1, Rebecca L Miller1
1Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110.
Neuron
|May 24, 2016
Summary
Selective four-repeat (4R) tau accumulation causes severe neurological symptoms in mice. Targeting 4R tau, potentially by skipping exon 10, offers a therapeutic strategy for related dementias.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Selective four-repeat (4R) tau deposition is observed in specific dementias.
- Mutations in the MAPT gene, specifically at exon 10, are linked to 4R tau pathology.
- Direct in vivo assessment of 4R tau toxicity has been lacking.
Purpose of the Study:
- To directly assess the in vivo toxicity of four-repeat (4R) tau.
- To investigate the potential of targeting 4R tau for therapeutic intervention.
Main Methods:
- Utilized human tau-expressing mice to increase 4R tau expression without altering total tau levels.
- Administered interventions to induce exon 10 skipping in vivo.
- Monitored behavioral abnormalities, tau phosphorylation, and tau aggregation states.
Main Results:
- Increased 4R tau expression led to more severe seizures and abnormal nesting behavior in mice.
- Elevated tau phosphorylation and a shift towards oligomeric tau species were observed.
- Successful in vivo induction of exon 10 skipping was demonstrated.
Conclusions:
- Four-repeat tau accumulation is directly toxic in vivo, causing significant neurological dysfunction.
- Targeting 4R tau, potentially through exon 10 skipping, is a viable therapeutic strategy for 4R tauopathies.
- This approach could eliminate disease-causing mutations in primary MAPT-related disorders.
