Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction

Project Summary/Abstract Postsynaptic kinase/phosphatase networks in amyloid b-induced synaptic dysfunction Impaired synaptic function and synapse loss are early hallmarks of Alzheimer’s Disease (AD). There is strong evidence that amyloid beta (Ab) leads to AD-related synapse dysfunction and cognitive impairment. For example, long-term potentiation (LTP), a key form of plasticity for learning and memory, is disrupted in mouse models harboring familial AD-linked mutations that lead to Ab accumulation. Even acute applications of soluble Ab oligomers block LTP within minutes and lead to synapse loss within days. It is increasingly appreciated that Ab hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression (LTD), or synapse weakening/elimination. LTP and LTD in the hippocampus are ultimately driven by insertion and removal of AMPA-type glutamate receptors (AMPAR) from synapses. Central to the signaling pathways regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatases signaling network that is coordinated by the scaffold protein AKAP79/150 and includes CaMKIIa, PKA, and PP2B/calcineurin (CaN). During the last funding period we made several important discoveries regarding how Ab engages local, postsynaptic LTD-associated signaling pathways to impair LTP. Central to the current proposal, we observed that either acute Ab application or prolonged Ab exposure in the 5xFAD mouse model of AD leads to accumulation of Ca2+-permeable AMPARs (CP-AMPARs) at hippocampal synapses. CP-AMPARs are normally excluded from synapses but can be trafficked to synapses downstream of AKAP-anchored PKA signaling to modify synaptic strength during plasticity in the healthy brain. However, in many cases, the incorporation of CP-AMPARs biases subsequent synaptic signaling toward LTD, consistent with Ab-triggered synapse depression and elimination. Thus, a new central premise established by the research previously funded by this multi-PI R01 is that Ca2+ influx through CP-AMPARs plays a previously overlooked, but key role in mediating Aβ synaptotoxicity. Additional data indicate that Ab may engage AKAP-PKA signaling via G-protein- coupled b2-adrenergic (b2AR) and/or group I mGluR receptors. During the next funding period we will test the overall hypothesis that b2AR/mGluR-AKAP-PKA signaling regulates synaptic recruitment of CP-AMPARs to mediate not only acute impacts of Ab associated with LTP inhibition but also chronic impacts leading to dendritic spine/excitatory synapse loss, long-term synaptic dysfunction, and cognitive impairments in vivo in 5xFAD mice.