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

Shira Knafo, Cristina Sánchez-Puelles, Ernest Palomer, Igotz Delgado, Jonathan E. Draffin, Janire Mingo, Tina Wahle, Kanwardeep Kaleka, Liping Mou, Inmaculada Pereda-Perez, Edvin Klosi, Erik B. Faber, Heidi M. Chapman, Laura Lozano-Montes, Ana Ortega-Molina, Lara Ordóñez-Gutiérrez, Francisco Wandosell, Jose Viña, Carlos G. Dotti, Randy A. HallRafael Pulido, Nashaat Z. Gerges, Andrew M. Chan, Mark R. Spaller, Manuel Serrano, César Venero, José A. Esteban

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)443-453
Number of pages11
JournalNature Neuroscience
Volume19
Issue number3
DOIs
StatePublished - 23 Feb 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank F. Valdivieso (Centro de Biologia Molecular "Severo Ochoa") for the App

Funding Information:
We thank F. Valdivieso (Centro de Biología Molecular “Severo Ochoa”) for the Appswe/lnd construct, W. Klein (Northwestern University) for the Aβ antibody (NU-1), D. Walsh (Harvard Institutes of Medicine) for expert advice and providing protocols, and members of the Esteban laboratory for critical reading of this manuscript. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (CSD-2010-00045, SAF-2011-24730 and SAF2014-57233-R to J.A.E.; SAF2010-15676, SAF2013-43902-R and SAF2015-62540-ERC to S.K.; SAF-2009-09129 to C.V.; SAF2009-12249-C02-01 to F.W.; CSD2010-00045 and SAF2010-14906 to C.G.D.; SAF2013-48812-R to R.P.). The laboratory of S.K. is supported by a grant from Alzheimer’s Association (NIRG-13-279533), from the Basque Ministry of Health (2013111138), from the University of the Basque Country (EHUrOPE14/03) and from Ikerbasque foundation. The laboratory of F.W. is also supported by CIBERNED (an initiative of ISCIII) and by EU-FP7-2009-CT222887 grant. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional Government of Madrid, Botín Foundation, Ramón Areces Foundation, and AXA Foundation. A.M.C. is funded by grants R01CA095063 and R21CA133669 from the US National Institutes of Health. T.W. is funded from the Federal Office for Scientific Affairs (IUAP P6/43) and Flemish Government’s Methusalem Grant. N.Z.G. is funded from the US National Institute on Aging (AG032320), Alzheimer’s Association and American Health Assistance Foundation (AHAF). S.K. was the recipient of a “Ramón y Cajal” contract from the Spanish Ministry of Science and Innovation and is now an IkerBasque Research Professor. C.S.-P. is a recipient of an FPI scholarship from the Spanish Ministry of Economy and Competitiveness (BES-2011-043464). J.M. is the recipient of a predoctoral fellowship (PRE_2014_1_285) from Gobierno Vasco, Departamento de Educación (Basque Country, Spain).

Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.

ASJC Scopus subject areas

  • Neuroscience (all)

Fingerprint

Dive into the research topics of 'PTEN recruitment controls synaptic and cognitive function in Alzheimer's models'. Together they form a unique fingerprint.

Cite this