Buck Institute for Research on Aging

Developing a KIBRA Therapeutic to Reverse Memory Loss in Tauopathy and Aging

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Synapse dysfunction and memory loss are common features in both the elderly and patients with Alzheimer’s disease (AD). Genetic variation in the gene that encodes KIBRA is linked to better memory performance and lower risk for AD. Mouse studies showed that depletion of KIBRA in the brain causes synapse dysfunction. Our work revealed reduced KIBRA protein levels in the brain in AD patients with dementia. We also discovered that KIBRA protein is reduced in the hippocampus of aged mice. These results suggest that loss of KIBRA protein in the brain may be the common mechanism underlying synapse dysfunction and memory loss in normal aging and AD.
We designed a small synthetic KIBRA-derived peptide to mimic the function of KIBRA at synapses. In this proposal, we will test the impact of the peptide on memory loss in both aged mice and in an AD-related transgenic mouse model using multiple behavioral tests. We will also investigate the effect of the peptide on synapse pathophysiology to gain insights into the mechanism by which the peptide works. Our long-term goal is to develop a novel therapeutic approach to treat synapse dysfunction and memory loss in both aging-related memory loss and dementia in AD.