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The Journal of Neuroscience, July 18, 2007, 27(29):7648-7653; doi:10.1523/JNEUROSCI.0395-07.2007

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Brief Communications
Aß Oligomer-Mediated Long-Term Potentiation Impairment Involves Protein Phosphatase 1-Dependent Mechanisms

Marlen Knobloch,^1 * Mélissa Farinelli,^2 * Uwe Konietzko,¹ Roger M. Nitsch,¹  and Isabelle M. Mansuy² 

¹Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland, and ²Brain Research Institute, University of Zurich and Department of Biology, Swiss Federal Institute of Technology, 8057 Zurich, Switzerland

Correspondence should be addressed to either of the following: Isabelle M. Mansuy, Brain Research Institute, University of Zurich/Eidgenössische Technische Hochschule Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Email: mansuy{at}hifo.unizh.ch; or Roger M. Nitsch, Division of Psychiatry Research, University of Zurich, August Forel-Strasse 1, 8008 Zurich, Switzerland, Email: nitsch{at}bli.unizh.ch

Amyloid ß (Aß) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. The mechanisms underlying such toxicity on synaptic functions are complex and not fully understood. Here, we provide the first evidence that these mechanisms involve protein phosphatase 1 (PP1). Using a novel transgenic mouse model expressing human APP with the Swedish and Arctic mutations that render Aß more prone to form oligomers (arcAß mice), we show that the LTP impairment induced by Aß oligomers can be fully reversed by PP1 inhibition in vitro. We further demonstrate that the genetic inhibition of endogenous PP1 in vivo confers resistance to Aß oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology.

Key words: impairment; PP1; oligomers; Aß-peptide; Alzheimer's disease; LTP

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Received Jan. 29, 2007; revised May 10, 2007; accepted May 10, 2007.

Correspondence should be addressed to either of the following: Isabelle M. Mansuy, Brain Research Institute, University of Zurich/Eidgenössische Technische Hochschule Zürich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, Email: mansuy{at}hifo.unizh.ch; or Roger M. Nitsch, Division of Psychiatry Research, University of Zurich, August Forel-Strasse 1, 8008 Zurich, Switzerland, Email: nitsch{at}bli.unizh.ch

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