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

88 Scopus citations

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

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