Presenter of 1 Presentation
SELECTIVE INHIBITION OF CASPASE-2 BLOCKS PRODUCTION OF DELTA-TAU314 AND RESTORES EXCITATORY NEUROTRANSMISSION IN NEURONS EXPRESSING MUTANT TAU LINKED TO FRONTOTEMPORAL DEMENTIA
Abstract
Aims
In 2016 the Ashe laboratory reported that caspase-2 mediated cleavage of tau reversibly impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. This discovery led us to develop and characterize a potent and selective caspase-2 inhibitor (1)
Methods
Using solid- and solution-phase peptide chemistry we prepared compound 1 as a single diastereomer along with both pure epimers of the best previously reported racemic, reversible covalent inhibitor, compound 2, and its inactive analog, compound 3. We have measured the effects of these three compounds on the activities of caspase-1, -2, -3, -6, -7, and -9 in vitro. To test whether the compounds can rescue synaptic deficits in a cellular model of frontotemporal dementia, we measured their effects on the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) in primary hippocampal cultures prepared from transgenic mice expressing P301S mutant tau whereas transgene negative littermates were used as controls. We have also tested the ability of compound 1 to affect the missorting of tau to dendritic spines.
Results
Compound 1 restores the amplitude and frequency of synaptic currents impaired by P301S tau more effectively than compound 2 and its inactive analog compound 3. Additionally, compound 1 completely halts the missorting of tau into dendritic spines.
Conclusions
We have designed, prepared, and characterized the first potent, selective, and neuroactive caspase-2 inhibitor (1) in cultured neurons and demonstrated that it can restore synaptic currents and halt the missorting of tau.