Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers

A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wildtype mice that promoted long-term potentiation. A key feature of the EE effect was activation of beta(2)-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid beta-protein (A beta) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a beta-adrenergic agonist without EE were protected from hippocampal impairment by A beta oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating beta-adrenoceptor signaling and mitigating synaptotoxicity of human A beta oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral beta-adrenergic agonists to lessen the effects of A beta accumulation during aging.