Aβ Oligomer-Mediated Long-Term Potentiation Impairment Involves Protein Phosphatase 1-Dependent Mechanisms

• DOI: 10.1523/jneurosci.0395-07.2007
• Publication Date: 2007-07-18T17:28:28Z
• Authors: Marlen Knobloch; Mélissa Farinelli; Uwe Konietzko; Roger M. Nitsch; Isabelle M. Mansuy
• Keywords: 0301 basic medicine; Patch-Clamp Techniques; Long-Term Potentiation; 610 Medicine & health; Mice, Transgenic; In Vitro Techniques; Hippocampus; Mice; 03 medical and health sciences; Microscopy, Electron, Transmission; Animals; Humans; Neurons; Analysis of Variance; Amyloid beta-Peptides; Age Factors; 2800 General Neuroscience; Excitatory Postsynaptic Potentials; Dose-Response Relationship, Radiation; 11359 Institute for Regenerative Medicine (IREM); Electric Stimulation; Gene Expression Regulation; Calcium-Calmodulin-Dependent Protein Kinases; Amyloid Precursor Protein Secretases; Calcium-Calmodulin-Dependent Protein Kinase Type 2

Amyloid β (Aβ) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP)in vivoandin 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 Aβ more prone to form oligomers (arcAβ mice), we show that the LTP impairment induced by Aβ oligomers can be fully reversed by PP1 inhibitionin vitro. We further demonstrate that the genetic inhibition of endogenous PP1in vivoconfers resistance to Aβ oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology.