Inhibition of hippocampal mossy fiber plasticity and episodic memory by human Aβ oligomers is prevented by enhancing cAMP signaling in Alzheimer's mice.

INTRODUCTION: Early episodic memory impairment in Alzheimer's disease (AD) is linked to synaptic dysfunction from amyloid β-protein oligomers (oAβ), particularly affecting the dentate gyrus mossy fiber-CA3 pathway. The APP(NL-G-F) mouse model exhibits early deficits in mossy fiber long-term potentiation (mf-LTP). METHODS: We administered the β-adrenergic receptor agonist isoproterenol (ISO) in vivo and phosphodiesterase type 4 inhibitor GSK356278 in vitro to assess their impact on mf-LTP and contextual fear memory. Fluorescence lifetime imaging (FLIM)-Förster resonance energy transfer (FRET) microscopy was used to visualize impaired and rescued cyclic adenosine monophosphate (cAMP) signaling in dentate gyrus neurons. RESULTS: ISO prevented mf-LTP impairment at 3-4 mo and improved memory by 7 mo. GSK356278 inhibited mf-LTP deficits in a dose-dependent manner. ISO also reduced hyperphosphorylation of synapsin I and microgliosis. DISCUSSION: These findings suggest that β-AR activation and phosphodiesterase 4 (PDE4) inhibition mitigate oAβ-induced memory deficits, supporting enhanced cAMP signaling as a therapeutic target for early AD. HIGHLIGHTS: Early episodic memory deficits in AD linked to oAβ-induced synaptic dysfunction. Isoproterenol and GSK356278 improve mossy fiber-LTP and fear memory deficits. FLIM-FRET shows treatments restore cAMP signaling in dentate gyrus neurons. Isoproterenol reduces synapsin I hyperphosphorylation and microgliosis. Enhancing cAMP signaling may help mitigate early memory deficits in AD.