PTEN recruitment controls synaptic and cognitive function in Alzheimer's models
| Autor: | Nashaat Z. Gerges, Erik B. Faber, Inmaculada Pereda-Pérez, Mark R. Spaller, Randy A. Hall, Jose Viña, Liping Mou, Lara Ordóñez-Gutiérrez, José A. Esteban, Cristina Sánchez-Puelles, Rafael Pulido, Andrew K Chan, Tina Wahle, Manuel Serrano, Janire Mingo, Heidi M Chapman, Francisco Wandosell, Ana Ortega-Molina, Shira Knafo, Kanwardeep Kaleka, Jonathan E. Draffin, Laura Lozano-Montes, Igotz Delgado, Edvin Klosi, César Venero, Ernest Palomer, Carlos G. Dotti |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Primary Cell Culture PDZ Domains Mice Transgenic Molecular neuroscience Biology Neurotransmission Synaptic Transmission Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Postsynaptic potential medicine Animals PTEN Gene Knock-In Techniques Amyloid beta-Peptides General Neuroscience PTEN Phosphohydrolase Long-term potentiation medicine.disease Rats Disease Models Animal 030104 developmental biology Synaptic fatigue Synaptic plasticity biology.protein Alzheimer's disease Cognition Disorders Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | NATURE NEUROSCIENCE r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA instname |
| ISSN: | 1546-1726 1097-6256 |
| DOI: | 10.1038/nn.4225 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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