Postsynaptic kinase/phosphatase networks in amyloid ?-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; A? vs. tau) there is strong genetic, biochemical, anatomical and electrophysiological evidence supporting that A? is sufficient to initiate cellular processes leading to severe synaptic pathology. For example sub-micromolar doses of A? acutely (within minutes) inhibit long-term potentiation (LTP), a form of synaptic plasticity critical for learning and memory. In addition, longer A? 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 A?-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 A?- induced LTP disruption, possibly through impaired NMDA receptor Ca2+ entry. It remains unclear whether these same signaling mechanisms mediate chronic A?-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 A? 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.
Postsynaptic kinase/phosphatase networks in amyloid ?-induced synaptic dysfunction In Alzheimer's disease (AD) overproduction of amyloid beta (A?) protein fragments from the amyloid precursor protein (APP) is thought to interfere with the normal signaling functions of brain synapses during aging to interfere with learning and memory and cause dementia. Elucidating how A? interferes with synaptic function is an important first step for understanding the mechanisms underlying cognitive impairments associated with AD and could result in the identification of novel drug targets and therapies. However, very little research to date has shed any light on the mechanisms by which A? engages and interacts with specific synaptic signaling pathways to cause neuronal dysfunction and cognitive impairment. Here, with the use of an innovative genetically engineered mouse model, we will test the novel idea that A? activates signaling that impairs synaptic and cognitive function through a protein called Calcineurin that is specifically anchored at synapses by a protein called AKAP150. Importantly, these studies will investigate whether targeted disruption of AKAP150-anchored Calcineurin signaling at synapses and/or interfering with some of its downstream targets could be worth exploring as a viable therapy for preventing synaptic and cognitive dysfunction in AD.
