期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 22, 页码 8740-8745出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206171109
关键词
brain disease; in vivo imaging
资金
- Deutsche Forschungsgemeinschaft [IRTG 1373]
- European Research Area-Net Program
- Schiedel Foundation
Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-beta (A beta) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca2+ imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of A beta may underlie this impairment. Indeed, we found that acute treatment with the gamma-secretase inhibitor LY-411575 reduces soluble A beta levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble A beta can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble A beta is crucial for hippocampal hyperactivity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据