Project Summary Abstract Postsynaptic kinase/phosphatase networks in amyloid β-induced synaptic dysfunction Alzheimer's disease (AD) is characterized by impaired synaptic function and synapse loss in key forebrain areas required for learning and memory, including the hippocampus. While the pathologic agent that causes AD remains contentious (amyloid-beta; Aβ vs. tau) there is strong genetic, biochemical, anatomical and electrophysiological evidence supporting that Aβ is sufficient to initiate cellular processes leading to severe synaptic pathology. For example sub-micromolar doses of Aβ acutely (within minutes) inhibit long-term potentiation (LTP), a form of synaptic plasticity critical for learning and memory. In addition, longer Aβ exposure (days to weeks) leads to depression and elimination of excitatory synapses through a process that requires NMDA receptor signaling. However, the downstream signaling networks that drive acute and chronic Aβ-mediated synaptic pathologies are only beginning to emerge and need to be further investigated. Strong preliminary data from our labs implicate several postsynaptic ser/thr kinases (CaMKII, DAPK1, PKA) and a phosphatase (calcineurin (CaN)) as key molecular players responsible for acute Aβ- induced LTP disruption, possibly through impaired NMDA receptor Ca2+ entry. It remains unclear whether these same signaling mechanisms mediate chronic Aβ-induced synaptic depression and elimination, but published and preliminary data presented here indicate that CaN activity is required. Importantly, all of these kinases and phosphatases interact with one another in a postsynaptic signaling network that integrates NMDAR activity to promote either LTP or LTD. Indeed, synaptic anchoring of PKA and CaN by the scaffold protein AKAP79/150 appears to be critical for promoting signaling crosstalk between PKA, CaN, DAPK1 and CaMKII at synaptic sites to establish normal LTP/LTD balance. In this multi-PI project we will test the hypothesis that Aβ causes acute (Aims 1 & 2) and chronic (Aims 3 & 4) synaptic dysfunction by perturbing the balance of this signaling network and its downstream effectors to favor LTD, leading to impaired LTP and synapse elimination.