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RESEARCH PRODUCT
PTEN recruitment controls synaptic and cognitive function in Alzheimer's models
Nashaat Z. GergesErik B. FaberInmaculada Pereda-pérezMark R. SpallerRandy A. HallJose ViñaLiping MouLara Ordóñez-gutiérrezJosé A. EstebanCristina Sánchez-puellesRafael PulidoAndrew K ChanTina WahleManuel SerranoJanire MingoHeidi M ChapmanFrancisco WandosellAna Ortega-molinaShira KnafoShira KnafoShira KnafoKanwardeep KalekaJonathan E. DraffinLaura Lozano-montesIgotz DelgadoEdvin KlosiCésar VeneroErnest PalomerCarlos G. Dottisubject
0301 basic medicinePrimary Cell CulturePDZ DomainsMice TransgenicMolecular neuroscienceBiologyNeurotransmissionSynaptic TransmissionMice03 medical and health sciences0302 clinical medicineAlzheimer DiseasePostsynaptic potentialmedicineAnimalsPTENGene Knock-In TechniquesAmyloid beta-PeptidesGeneral NeurosciencePTEN PhosphohydrolaseLong-term potentiationmedicine.diseaseRatsDisease Models Animal030104 developmental biologySynaptic fatigueSynaptic plasticitybiology.proteinAlzheimer's diseaseCognition DisordersNeuroscience030217 neurology & neurosurgerydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-01-18 | Nature Neuroscience |