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

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

doi:10.1038/nn.4225

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

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. HallRafael Pulido, Nashaat Z. Gerges, Andrew M. Chan, Mark R. Spaller, Manuel Serrano, César Venero, José A. Esteban

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	443-453
Number of pages	11
Journal	Nature Neuroscience
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/nn.4225
State	Published - 23 Feb 2016
Externally published	Yes

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© 2016 Nature America, Inc. All rights reserved.

ASJC Scopus subject areas

General Neuroscience

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Knafo, S., Sánchez-Puelles, C., Palomer, E., Delgado, I., Draffin, J. E., Mingo, J., Wahle, T., Kaleka, K., Mou, L., Pereda-Perez, I., Klosi, E., Faber, E. B., Chapman, H. M., Lozano-Montes, L., Ortega-Molina, A., Ordóñez-Gutiérrez, L., Wandosell, F., Viña, J., Dotti, C. G., ... Esteban, J. A. (2016). PTEN recruitment controls synaptic and cognitive function in Alzheimer's models. Nature Neuroscience, 19(3), 443-453. https://doi.org/10.1038/nn.4225

@article{8d653b1afd5e42f8824f2b3cd41854d3,

title = "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.",

author = "Shira Knafo and Cristina S{\'a}nchez-Puelles and Ernest Palomer and Igotz Delgado and Draffin, {Jonathan E.} and Janire Mingo and Tina Wahle and Kanwardeep Kaleka and Liping Mou and Inmaculada Pereda-Perez and Edvin Klosi and Faber, {Erik B.} and Chapman, {Heidi M.} and Laura Lozano-Montes and Ana Ortega-Molina and Lara Ord{\'o}{\~n}ez-Guti{\'e}rrez and Francisco Wandosell and Jose Vi{\~n}a and Dotti, {Carlos G.} and Hall, {Randy A.} and Rafael Pulido and Gerges, {Nashaat Z.} and Chan, {Andrew M.} and Spaller, {Mark R.} and Manuel Serrano and C{\'e}sar Venero and Esteban, {Jos{\'e} A.}",

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doi = "10.1038/nn.4225",

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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 2016, 'PTEN recruitment controls synaptic and cognitive function in Alzheimer's models', Nature Neuroscience, vol. 19, no. 3, pp. 443-453. https://doi.org/10.1038/nn.4225

TY - JOUR

T1 - PTEN recruitment controls synaptic and cognitive function in Alzheimer's models

AU - Knafo, Shira

AU - Sánchez-Puelles, Cristina

AU - Palomer, Ernest

AU - Delgado, Igotz

AU - Draffin, Jonathan E.

AU - Mingo, Janire

AU - Wahle, Tina

AU - Kaleka, Kanwardeep

AU - Mou, Liping

AU - Pereda-Perez, Inmaculada

AU - Klosi, Edvin

AU - Faber, Erik B.

AU - Chapman, Heidi M.

AU - Lozano-Montes, Laura

AU - Ortega-Molina, Ana

AU - Ordóñez-Gutiérrez, Lara

AU - Wandosell, Francisco

AU - Viña, Jose

AU - Dotti, Carlos G.

AU - Hall, Randy A.

AU - Pulido, Rafael

AU - Gerges, Nashaat Z.

AU - Chan, Andrew M.

AU - Spaller, Mark R.

AU - Serrano, Manuel

AU - Venero, César

AU - Esteban, José A.

PY - 2016/2/23

Y1 - 2016/2/23

N2 - 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.

AB - 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.

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DO - 10.1038/nn.4225

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AN - SCOPUS:84959140220

SN - 1097-6256

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SP - 443

EP - 453

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 3

ER -

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

Abstract

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ASJC Scopus subject areas

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