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Nat Neurosci. 2016 Mar;19(3):443-53. doi: 10.1038/nn.4225. Epub 2016 Jan 18.

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.

Author information

1
Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
2
Unidad de Biofísica CSIC-UPV/EHU, Campus Universidad del País Vasco, Leioa, Spain.
3
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
4
Biocruces Health Research Institute, Barakaldo, Spain.
5
VIB Center for the Biology of Disease and Center for Human Genetics, University of Leuven (Katholieke University of Leuven), Leuven, Belgium.
6
IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
7
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
8
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
9
Department of Psychobiology, Universidad Nacional de Educación a Distancia, Madrid, Spain.
10
Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
11
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
12
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED).
13
Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain.
14
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

Abstract

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

PMID:
26780512
DOI:
10.1038/nn.4225
[Indexed for MEDLINE]

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