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The APP<jats:sup>NL\u2010G\u2010F<\/jats:sup> mouse model exhibits early deficits in mossy fiber long\u2010term potentiation (mf\u2010LTP).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We administered the \u03b2\u2010adrenergic receptor agonist isoproterenol (ISO) in vivo and phosphodiesterase type 4 inhibitor GSK356278 in vitro to assess their impact on mf\u2010LTP and contextual fear memory. Fluorescence lifetime imaging (FLIM)\u2010F\u00f6rster resonance energy transfer (FRET) microscopy was used to visualize impaired and rescued cyclic adenosine monophosphate (cAMP) signaling in dentate gyrus neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>ISO prevented mf\u2010LTP impairment at 3\u20134 mo and improved memory by 7 mo. GSK356278 inhibited mf\u2010LTP deficits in a dose\u2010dependent manner. ISO also reduced hyperphosphorylation of synapsin I and microgliosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These findings suggest that \u03b2\u2010AR activation and phosphodiesterase 4 (PDE4) inhibition mitigate oA\u03b2\u2010induced memory deficits, supporting enhanced cAMP signaling as a therapeutic target for early AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Early episodic memory deficits in AD linked to oA\u03b2\u2010induced synaptic dysfunction.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Isoproterenol and GSK356278 improve mossy fiber\u2010LTP and fear memory deficits.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>FLIM\u2010FRET shows treatments restore cAMP signaling in dentate gyrus neurons.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Isoproterenol reduces synapsin I hyperphosphorylation and microgliosis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Enhancing cAMP signaling may help mitigate early memory deficits in AD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70194","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T23:55:04Z","timestamp":1745970904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inhibition of hippocampal mossy fiber plasticity and episodic memory by human A\u03b2 oligomers is prevented by enhancing cAMP signaling in Alzheimer's mice"],"prefix":"10.1002","volume":"21","author":[{"given":"Shan\u2010Xue","family":"Jin","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases Department of Neurology Harvard Medical School and Brigham and Women's Hospital  Boston Massachusetts 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