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

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.

• Authors: 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 Hall, Rafael Pulido, Nashaat Z Gerges, Andrew M Chan, Mark R Spaller, Manuel Serrano, César Venero, José A Esteban
• Journal: Nature neuroscience (Nat Neurosci) Vol. 19 Issue 3 Pg. 443-53 (Mar 2016) ISSN: 1546-1726 [Electronic] United States
• PMID: 26780512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• PTEN Phosphohydrolase

Topics

• Alzheimer Disease (complications, metabolism, physiopathology)
• Amyloid beta-Peptides (toxicity)
• Animals
• Cognition Disorders (complications, physiopathology)
• Disease Models, Animal
• Gene Knock-In Techniques
• Mice
• Mice, Transgenic
• PDZ Domains (genetics, physiology)
• PTEN Phosphohydrolase (antagonists & inhibitors, genetics, physiology)
• Primary Cell Culture
• Rats
• Synaptic Transmission (drug effects, physiology)