Pterosin D-activated protein kinase A mitigates Alzheimer's disease in 5xFAD mice

BackgroundProtein kinase A (PKA) is a key activator of cAMP response element-binding protein signaling; it plays a pivotal role in cognition, memory, and adult neurogenesis. Phosphodiesterase (PDE) inhibitors that indirectly activate PKA through cAMP are promising candidates for Alzheimer's disease (AD) therapeutics.ObjectiveWe examined whether pterosins bind directly to PKA as activators and enhance cognition and memory.MethodsWe investigated PKA phosphorylation and performed <i>in silico</i> docking analysis using the cAMP-binding domains (CBD1, CBD2) of bovine PKA. Our focus was on exploring the effects of oral pterosin D on learning and memory in a 5xFAD mouse model of AD.ResultsWe demonstrated that C3-hydroxylated pterosins directly activated PKA in neuronal cells but not in astrocytes and did not affect intracellular cAMP levels or inhibit PDE. <i>In silico</i> modeling implied that C3-hydroxylated pterosins fitted the CBD of PKA. Pterosins enhanced long-term potentiation mossy fiber-CA1 in the mouse hippocampus without affecting normal synaptic transmission. Pterosins more potently accelerate neuronal proliferation and neurite outgrowth in primary mouse cortical neurons than dibutyryl-cAMP does. Pterosin D significantly restored cognition and memory in 5xFAD mice on the Morris water maze.ConclusionsC3-hydroxylated pterosins, as activators of PKA, have substantial potential as disease-modifying/-slowing therapeutic agent for AD.