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 APPNL-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.