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. PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Nat Neurosci. 2016 Mar;19(3):443-53. Epub 2016 Jan 18 PubMed.

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Comments

  1. This is an interesting and thorough study, whose experimental outcomes are pretty clear.

    One question one could ask is why chronic treatment with the PTEN inhibitor is necessary to improve the behavioral outcomes. There is no change in pAKT in the chronic treatment paradigm and if the effects of PTEN are modifying local signaling at the synapse, then acute treatment should be sufficient to measure a treatment benefit.

    In the future, the authors may want to measure the PTEN substrate PIP3 in any of their preparations to verify drug action at this level.  

    The story, while provocative, remains incomplete so long as the PDZ-containing effector(s) that mediate the synaptic effects of the therapeutic peptide remain unknown. However, the authors report that their PTEN-PDZ peptide interacted with four of 10 PDZ domains, hence it may be a challenge to obtain this level of mechanistic detail. 

    View all comments by Gary Landreth

  2. The exact mechanism of Aβ-induced depression of synaptic transmission is still mysterious. As it is possibly at the base of memory loss in Alzheimer’s disease, it is particularly important to understand its molecular mechanism.

    Esteban et al. make an important step forward in demonstrating that inhibition of PTEN rescued normal synaptic function and cognition in cellular and animal models of Alzheimer’s disease. By finding that the Aβ induced synaptic toxicity and cognitive dysfunction depends crucially on the recruitment of PTEN to synapses through a specific protein interaction domain (PDZ-binding domain), they advance our understanding of this phenomenon and open a new way to prevent Aβ-induced synaptic toxicity through inhibition of PTEN-PDZ interactions. Of particular interest is the finding that peptides that mimic the PTEN-DZ ligand protect against Aβ-induced synaptic toxicity.

    Indeed, the authors found that it is sufficient to specifically target PDZ-dependent interactions of PTEN—preserving its catalytic activity, thus most of PTEN’s normal functions—to disengage the cascade of events triggered by Aβ, therefore preventing synaptic and cognitive dysfunction.

    View all comments by Daniel Choquet

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