Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2013 Mar 6;77(5):929-41. doi: 10.1016/j.neuron.2012.12.040.
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 wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) 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 β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.
人类大脑衰老的一个核心问题是认知丰富是否会减缓阿尔茨海默病变化的发展。在这里，我们表明，长时间暴露于丰富的环境（EE）促进了野生型小鼠海马体内的信号转导，从而促进了长时程增强。EE 效应的一个关键特征是β2-肾上腺素能受体的激活和下游 cAMP/PKA 信号转导。这种 EE 途径可防止从 AD 皮层中分离出的淀粉样 β 蛋白（Aβ）的可溶性寡聚物抑制长时程增强。EE 在年轻和中年野生型小鼠中均具有保护作用。与有氧运动相比，接触新奇事物可提供更大的保护。慢性给予β-肾上腺素能激动剂而不进行 EE 的小鼠可免受 Aβ寡聚物对海马损伤的影响。因此，EE 通过激活β-肾上腺素能受体信号转导并减轻人 Aβ寡聚物的突触毒性，增强海马突触可塑性。这些机制上的见解支持长时间暴露于认知新奇事物和/或口服β-肾上腺素能激动剂，以减轻衰老过程中 Aβ积累的影响。
