Neuroscience Mind Games

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

The losses of cognitive capacity and memory are the key symptoms of Alzheimer’s disease, and studies have suggested that cognitive stimulation may ameliorate these symptoms. Transgenic mice that produce the toxic fragment Aβ by processing human APP (and are a model of early-onset Alzheimer’s disease) show improvements in cognitive defects when exposed to an enriched environment (EE). Wild-type mice exposed to EE exhibit a reduced threshold for long-term potentiation (LTP), which is associated with increased β-adrenergic receptor (β-AR) and cAMP signaling. To better model late-onset Alzheimer’s disease and eliminate effects on APP processing, Li et al. analyzed the electrophysiological and biochemical changes in hippocampi of mice kept in standard housing (SH) or EE, following exposure of the slices to Aβ. The addition of Aβ to hippocampal slice preparations resulted in inhibition of LTP, an effect that was prevented by exposure of young or adult mice to EE, although adult mice required a longer exposure to EE than did the young mice. Pharmacological activation of cAMP signaling also prevented the impairment of LTP by Aβ in the hippocampi from mice kept in SH, and application of a nonselective β-AR antagonist or a β₂-AR–selective antagonist prevented EE-mediated enhancement of LTP. Prolonged feeding of a nonspecific β-AR agonist to mice kept in SH prevented Aβ-mediated inhibition of LTP, whereas feeding a nonspecific β-AR antagonist prevented EE from protecting against Aβ-mediated inhibition of LTP. The abundance of β₂-AR, but not that of other β-ARs, or dopamine, serotonin, or muscarinic acetylcholine receptors, was higher in synaptosomal preparations from the hippocampi of EE mice than those from SH mice. Exposure of the hippocampal slices from SH mice to Aβ reduced the abundance of β₂-AR in synaptosomal preparations, and Aβ promoted the internalization of β₂-AR in cultured rat hippocampal neurons. Thus, these data suggest that cognitive enrichment or early, chronic treatment with β₂-AR agonists may prevent or reduce the progression of symptoms associated with Aβ toxicity and that these effects are independent of effects on APP processing.

S. Li, M. Jin, D. Zhang, T. Yang, T. Koeglsperger, H. Fu, D. J. Selkoe, Environmental novelty activates β₂-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers. Neuron 77, 929–941 (2013). [PubMed]

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