Faculty Collaboration Database

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Nat Neurosci 2016 Mar;19(3):443-53

Date

01/19/2016

Pubmed ID

26780512

DOI

10.1038/nn.4225

Scopus ID

2-s2.0-84959140220 (requires institutional sign-in at Scopus site)   110 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.

Author List

Knafo S, Sánchez-Puelles C, Palomer E, Delgado I, Draffin JE, Mingo J, Wahle T, Kaleka K, Mou L, Pereda-Perez I, Klosi E, Faber EB, Chapman HM, Lozano-Montes L, Ortega-Molina A, Ordóñez-Gutiérrez L, Wandosell F, Viña J, Dotti CG, Hall RA, Pulido R, Gerges NZ, Chan AM, Spaller MR, Serrano M, Venero C, Esteban JA

Author

Nashaat Gerges PhD Chair, Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Amyloid beta-Peptides
Animals
Cognition Disorders
Disease Models, Animal
Gene Knock-In Techniques
Mice
Mice, Transgenic
PDZ Domains
PTEN Phosphohydrolase
Primary Cell Culture
Rats
Synaptic Transmission