Project Summary Alzheimer’s disease (AD) is the most common form of dementia, with growing prevalence as the aging population continues to grow. Pathologically, this neurodegenerative disease is characterized by amyloid-β (Aβ) plaques and tau tangles. Acute application of Aβ has been shown to inhibit NMDA receptor (NMDAR)- dependent long-term potentiation (LTP, a key form of neuronal plasticity critical for learning and memory), and chronic Aβ exposure caused long-term depression (LTD) and elimination of excitatory synapses. Normal LTD requires the protein phosphatase Calcineurin (CaN) and pharmacological inhibition of CaN prevents Aβ- mediated LTP inhibition and synapse loss in rodent models. However, we not know where in the complex organization and architecture of the nervous system CaN is acting to promote these deleterious impacts of Ab on synaptic function. Here I will test the novel hypothesis that LTP inhibition, excitiatory synapse loss, and impaired cognition associated with mouse models of AD are due to Aβ triggering aberrant postsynaptic CaN activation in hippocampal pyramidal neurons. I will further test whether CaN that is specifically localized to postsynaptic sites by the scaffolding protein AKAP79/150 is responsible for mediating these synaptotoxic effects of Aβ at the molecular, cellular and behavioral levels in an effort to uncover potentially new therapeutic targets.