Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, China.
Neurobiol Dis. 2020 Feb;134:104617. doi: 10.1016/j.nbd.2019.104617. Epub 2019 Oct 24.
As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.
作为人类认知能力进行性下降的最常见原因，阿尔茨海默病（AD）已被深入研究，但导致其严重突触功能障碍的机制仍不清楚。在这里，我们证实，让野生型小鼠置身于丰富环境（EE）中，可促进海马体中的信号传递，从而增强长时程增强（LTP）。将标准环境中饲养的小鼠的海马体暴露于可溶性 Aβ 寡聚体中会损害 LTP，但 EE 可完全预防这种损害。从机制上讲，EE 带来的关键分子特征是 miRNA-132 的上调和组蛋白去乙酰化酶（HDAC）信号的抑制。具体而言，可溶性 Aβ 寡聚体降低了培养的原代神经元中的 miR-132 表达并增加了 HDAC3 水平。此外，我们提供的证据表明，HDAC3 是 miR-132 的直接靶标。在标准环境中饲养的小鼠中过表达 miR-132 或注射 HDAC3 抑制剂可模拟 EE 的益处，即在增强海马体 LTP 和预防 Aβ 寡聚体体内损伤方面发挥作用。我们得出结论，EE 通过上调 miRNA-132 和降低 HDAC3 信号来增强海马体的突触可塑性，从而抵消了人类 Aβ 寡聚体的突触毒性。我们的发现为长时间接触认知新奇事物和/或表观遗传调节提供了依据，以减轻人类大脑衰老过程中 Aβ 积累的进行性影响。
