The role of caspase-2 cleavage of tau in synaptic plasticity
Many neurodegenerative diseases are characterized by the abnormal accumulation of misfolded tau protein in neurons. Caspase-2 is a protease which has been shown to mediate long-term depression (LTD), a form of synaptic plasticity in which AMPA receptors are removed from dendritic spines, leading to decreased synaptic efficacy. Our lab recently produced a novel mouse model with a mutation in tau (aspartame->303->glutamate) which prevents caspase-2-mediated cleavage of tau. Our unpublished data indicates that this mutation blocks LTD. However, the effect of this mutation on long-term potentiation, the insertion of new AMPA receptors into spines, was unknown. In this project we tested the role of of caspase-2 cleavage of tau on LTP using slice electrophysiology using wild type and homozygous mutant D303E mice. Our recent data indicates that this mutation does not effect LTP. As LTP and LTD are common models for human memory, the lack of effect of this mutation on LTP while blocking LTD suggests that caspase-2 may be an effective drug-target for treating dementia in tauopathic neurodegenerative diseases.