| First Author | Busche MA | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 22 | Pages | 8740-5 |
| PubMed ID | 22592800 | Mgi Jnum | J:184752 |
| Mgi Id | MGI:5426283 | Doi | 10.1073/pnas.1206171109 |
| Citation | Busche MA, et al. (2012) Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 109(22):8740-5 |
| abstractText | 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 (Abeta) 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 Ca(2+) 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 Abeta may underlie this impairment. Indeed, we found that acute treatment with the gamma-secretase inhibitor LY-411575 reduces soluble Abeta levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Abeta 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 Abeta is crucial for hippocampal hyperactivity. |
