Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction

Impaired excitatory synaptic function and synapse loss are early hallmarks of Alzheimer's disease (AD). There is strong biochemical, genetic, physiological, and anatomical evidence that the accumulation of soluble amyloid beta (Aβ) oligomers in the brain leads to AD-related synapse dysfunction and cognitive impairment. Long-term potentiation (LTP), a key form of synaptic plasticity for learning and memory, is disrupted in several mouse models harboring familial early-onset AD-linked mutations that lead to Aβ accumulation, and even acute applications of Aβ oligomers block LTP within minutes and promote synapse loss within days. How does Aβ cause such profound synaptic dysfunction? It is increasingly appreciated that Aβ hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression (LTD) and eventual synapse elimination. LTP and LTD in the hippocampus are ultimately driven by insertion and removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from synapses, respectively, in response to Ca²⁺ signals generated by N-methyl-d-aspartate-type glutamate receptors or L-type voltage-gated Ca²⁺ channels. Central to the signaling pathways regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatase signaling network that is coordinated by the scaffold protein A-kinase anchoring protein (AKAP) 79/150 (human79/rodent150; AKAP5/Akap5 gene). This AKAP-organized signalosome includes N-methyl-d-aspartate-type glutamate receptors, AMPARs, L-type voltage-gated Ca²⁺ channels, G-protein-coupled receptors, adenylyl cyclase, the cyclic adenosine mono-phosphate (cAMP)-dependent protein kinase, and the Ca²⁺-calmodulin-dependent protein phosphatase 2B/calcineurin. This minireview will highlight recent findings that Gαs-coupled β₂-adrenergic and Gαq-coupled group 1 metabotropic glutamate (mGlu1/5) receptors signal through AKAP79/150-anchored cAMP-dependent protein kinase and protein phosphatase 2B/calcineurin to mediate multiple aspects of Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: Recent studies reveal that amyloid beta engages A-kinase anchoring protein-scaffolded G-protein-coupled receptor signaling pathways to disrupt synaptic plasticity and promote synapse loss. These pathways contain several potential therapeutic targets involved in both local cAMP-dependent protein kinase and calcineurin/protein phosphatase 2B (CaN) signaling that regulates L-type voltage-gated calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and N-methyl-d-aspartate receptors to impair synaptic plasticity as well as distal CaN signaling to the nucleus that regulates gene expression to drive synapse loss.