Work

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

Year: 2026

Type: review

Abstract: 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 (FAD)-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 AMPA-type glutamate receptors (AMPARs) from synapses, respectively, in response to Ca 2+ signals generated by NMDA-type glutamate receptors (NMDARs) or L-type voltage-gated Ca 2+ channels (LTCCs). 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 NMDARs, AMPARs, LTCCs, G-protein-coupled receptors (GPCRs), adenylyl cyclase (AC), the cAMP-dependent protein kinase (PKA), and the Ca 2+ -calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). This mini-review will highlight recent findings that Gαs-coupled β 2 -adrenergic (β 2 AR) and Gαq-coupled group 1 metabotropic glutamate (mGlu1/5) receptors signal through AKAP79/150-anchored PKA and CaN to mediate multiple aspects of Aβ synaptotoxicity.

Source: Molecular Pharmacology

DOI: 10.1016/j.molpha.2026.100141

Authors: Laura Koek, Ha-Neul Jo, Matthew J. Kennedy, Mark L. Dell’Acqua

Institution: University of Colorado Anschutz

Language: English

Topic: Neuroscience and Neuropharmacology Research

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,600