Abstract

The project objectives include the development tools for drug discovery and the application of these tools for the identification of novel compounds to remediate memory impairment. Based on a very successful first year of the network we are on track to proceed with the proposed program. Under the objective of tau clearance we have developed a farnesylation assay in brain that will provide critical information for transitioning to a human clinical trial of Lonafarnib. Under the objective of inhibiting tau spread we have synthesized eight new GAG sulfotransferase inhibitor analogues and two of these inhibitors are likely to function as irreversible inhibitors. We are testing their effects tau internalization, tau secretion, and transneuronal spreading. Under the objective of developing a neuronal activity assay in mice using calcium imaging to directly assess neural circuitry, we have demonstrated that we can achieve widespread expression of acalcium indicator in cortical neurons and measure the responses of populations of individual neurons using 2-photon laser scanning microscopy in rTg4510 mice. A physiological readout for drug response will provide a completely novel reagent. Under the objective of developing electrophysiologic assays in human cultured neurons to assess axonal conduction signals and synaptic transmission for testing drug candidates we have automated the detection these parameters. We can now survey an entire array to compute all of the conduction velocities, synaptic latencies and efficiencies. We have extended the analysis to compute the per neuron change in information transmitted within a single array after delivery of a drug.