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Title: PTEN recruitment controls synaptic and cognitive function in Alzheimer's models
Authors: Knafo, Shira ×
Sánchez-Puelles, Cristina
Palomer, Ernest
Delgado, Igotz
Draffin, Jonathan E
Mingo, Janire
Wahle, Tina
Kaleka, Kanwardeep
Mou, Liping
Pereda-Perez, Inmaculada
Klosi, Edvin
Faber, Erik B
Chapman, Heidi M
Lozano-Montes, Laura
Ortega-Molina, Ana
Ordóñez-Gutiérrez, Lara
Wandosell, Francisco
Viña, Jose
Dotti, Carlos
Hall, Randy A
Pulido, Rafael
Gerges, Nashaat Z
Chan, Andrew M
Spaller, Mark R
Serrano, Manuel
Venero, César
Esteban, José A #
Issue Date: Mar-2016
Publisher: Nature America Inc.
Series Title: Nature Neuroscience vol:19 issue:3 pages:443-53
Article number: 10.1038/nn.4225
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.
URI: 
ISSN: 1097-6256
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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