Zane Crabtree

The neurons of patients with Lewy body Diseases (LBD) often contain high levels of misfolded tau protein and α-synuclein, and many patients develop dementia. Caspase-2 is a cysteine-aspartic protease that has been shown to mediate long-term depression (LTD), a form of synaptic plasticity characterized by the internalization of AMPA receptors, which leads to synaptic weakening that is believed to underlie forgetting. Recently, we found that in mice, caspase-2 cleaves tau at aspartate 303, and this process mediates LTD (unpublished data). The A53T α-synuclein variant linked to familial Parkinson’s disease increases the internalization of AMPA receptors in a tau-dependent manner, but the role of caspase-2 and the effect of this process on LTD are unknown.  Here, we provide evidence to test the hypothesis that in LBD caspase-2 cleavage of tau leads to excessive synaptic weakening. We measured LTD in hippocampal slices from transgenic mice expressing A53T α-synuclein and non-transgenic littermates in which mouse tau was wild-type or mutated (aspartate-303-glutamate) to render tau resistant to caspase-2 cleavage. Our preliminary data indicate that in mice with wild-type tau, A53T α-synuclein is associated with enhanced LTD, supporting our hypothesis that there is excessive synaptic weakening in LBD. We are obtaining LTD measurements in mice with caspase-2 resistant tau to determine if this enhanced LTD depends on caspase-2 cleavage of tau.