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

Authors: Knafo, S  Sanchez-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  Ordonez-Gutierrez, L  Wandosell, F  Vina, J  Dotti, CG  Hall, RA  Pulido, R  Gerges, NZ  Chan, AM  Spaller, MR  Serrano, M  Venero, C  Esteban, JA 
Citation: Knafo S, etal., Nat Neurosci. 2016 Mar;19(3):443-53. doi: 10.1038/nn.4225. Epub 2016 Jan 18.
Pubmed: (View Article at PubMed) PMID:26780512
DOI: Full-text: DOI:10.1038/nn.4225

Dyshomeostasis of amyloid-beta peptide (Abeta) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Abeta 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 Abeta-induced depression. Mechanistically, Abeta 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 Abeta-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Abeta-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Abeta signaling.

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RGD Object Information
RGD ID: 11352897
Created: 2016-07-20
Species: All species
Last Modified: 2016-07-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.