Cofilin is a protein that regulates the organization of the neuronal actin cytoskeleton, which functions in cell movement, shape changes, membrane addition and removal and secretion. Included among these functions is the insertion in the postsynaptic membrane of neurons in the brain of specific receptors, which alter intracellular communication and are involved in remodeling the circuitry for memory and learning, a phenomenon called plasticity. Cofilin is inactivated by the addition of phosphate onto a single amino acid residue and it is activated by removal of the phosphate. In cells under stress, cofilin becomes over active and binds to filaments of actin, causing them to bundle together forming rods. When this occurs in stressed neurons, the rods block transport within axons and dendrites and cause loss of function of synapses distal to the rod. Cofilin-actin rods are a newly recognized pathology of Alzheimer's disease (AD). Because of their rapid formation (minutes) in response to a variety of neurodegenerative stimuli, including anoxia, oxidative stress, excess glutamate and exposure to natural forms of the AD-associated amyloid beta peptide, rods may be an important initiator of synaptic loss and mediate other changes that lead to AD pathology. We have recently identified sites on cofilin that when mutated, block its ability to accumulate into rods. This proposal is designed to generate peptidomimetic reagents that target that site to prevent rod formation, as well as to target cofilin domains required for its phosphoregulation and actin binding. With these reagents we propose to determine if it is rod formation, effects on receptor insertion, or both that result in altered electrophysiological properties of brain slices subjected to exposure to amyloid beta peptides, a presumed initiator of neurodegeneration in many AD patients.