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

Bibliographical note

Funding Information:
We thank F. Valdivieso (Centro de Biologia Molecular "Severo Ochoa") for the App

Funding Information:
We thank F. Valdivieso (Centro de Biología Molecular “Severo Ochoa”) for the Appswe/lnd construct, W. Klein (Northwestern University) for the Aβ antibody (NU-1), D. Walsh (Harvard Institutes of Medicine) for expert advice and providing protocols, and members of the Esteban laboratory for critical reading of this manuscript. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (CSD-2010-00045, SAF-2011-24730 and SAF2014-57233-R to J.A.E.; SAF2010-15676, SAF2013-43902-R and SAF2015-62540-ERC to S.K.; SAF-2009-09129 to C.V.; SAF2009-12249-C02-01 to F.W.; CSD2010-00045 and SAF2010-14906 to C.G.D.; SAF2013-48812-R to R.P.). The laboratory of S.K. is supported by a grant from Alzheimer’s Association (NIRG-13-279533), from the Basque Ministry of Health (2013111138), from the University of the Basque Country (EHUrOPE14/03) and from Ikerbasque foundation. The laboratory of F.W. is also supported by CIBERNED (an initiative of ISCIII) and by EU-FP7-2009-CT222887 grant. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional Government of Madrid, Botín Foundation, Ramón Areces Foundation, and AXA Foundation. A.M.C. is funded by grants R01CA095063 and R21CA133669 from the US National Institutes of Health. T.W. is funded from the Federal Office for Scientific Affairs (IUAP P6/43) and Flemish Government’s Methusalem Grant. N.Z.G. is funded from the US National Institute on Aging (AG032320), Alzheimer’s Association and American Health Assistance Foundation (AHAF). S.K. was the recipient of a “Ramón y Cajal” contract from the Spanish Ministry of Science and Innovation and is now an IkerBasque Research Professor. C.S.-P. is a recipient of an FPI scholarship from the Spanish Ministry of Economy and Competitiveness (BES-2011-043464). J.M. is the recipient of a predoctoral fellowship (PRE_2014_1_285) from Gobierno Vasco, Departamento de Educación (Basque Country, Spain).

Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.

ASJC Scopus subject areas

Neuroscience (all)

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10.1038/nn.4225

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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.}",

note = "Funding Information: We thank F. Valdivieso (Centro de Biologia Molecular {"}Severo Ochoa{"}) for the App Funding Information: We thank F. Valdivieso (Centro de Biolog{\'i}a Molecular “Severo Ochoa”) for the Appswe/lnd construct, W. Klein (Northwestern University) for the Aβ antibody (NU-1), D. Walsh (Harvard Institutes of Medicine) for expert advice and providing protocols, and members of the Esteban laboratory for critical reading of this manuscript. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (CSD-2010-00045, SAF-2011-24730 and SAF2014-57233-R to J.A.E.; SAF2010-15676, SAF2013-43902-R and SAF2015-62540-ERC to S.K.; SAF-2009-09129 to C.V.; SAF2009-12249-C02-01 to F.W.; CSD2010-00045 and SAF2010-14906 to C.G.D.; SAF2013-48812-R to R.P.). The laboratory of S.K. is supported by a grant from Alzheimer{\textquoteright}s Association (NIRG-13-279533), from the Basque Ministry of Health (2013111138), from the University of the Basque Country (EHUrOPE14/03) and from Ikerbasque foundation. The laboratory of F.W. is also supported by CIBERNED (an initiative of ISCIII) and by EU-FP7-2009-CT222887 grant. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional Government of Madrid, Bot{\'i}n Foundation, Ram{\'o}n Areces Foundation, and AXA Foundation. A.M.C. is funded by grants R01CA095063 and R21CA133669 from the US National Institutes of Health. T.W. is funded from the Federal Office for Scientific Affairs (IUAP P6/43) and Flemish Government{\textquoteright}s Methusalem Grant. N.Z.G. is funded from the US National Institute on Aging (AG032320), Alzheimer{\textquoteright}s Association and American Health Assistance Foundation (AHAF). S.K. was the recipient of a “Ram{\'o}n y Cajal” contract from the Spanish Ministry of Science and Innovation and is now an IkerBasque Research Professor. C.S.-P. is a recipient of an FPI scholarship from the Spanish Ministry of Economy and Competitiveness (BES-2011-043464). J.M. is the recipient of a predoctoral fellowship (PRE_2014_1_285) from Gobierno Vasco, Departamento de Educaci{\'o}n (Basque Country, Spain). Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",

year = "2016",

month = feb,

day = "23",

doi = "10.1038/nn.4225",

language = "English",

volume = "19",

pages = "443--453",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "3",

}

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.

N1 - Funding Information: We thank F. Valdivieso (Centro de Biologia Molecular "Severo Ochoa") for the App Funding Information: We thank F. Valdivieso (Centro de Biología Molecular “Severo Ochoa”) for the Appswe/lnd construct, W. Klein (Northwestern University) for the Aβ antibody (NU-1), D. Walsh (Harvard Institutes of Medicine) for expert advice and providing protocols, and members of the Esteban laboratory for critical reading of this manuscript. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (CSD-2010-00045, SAF-2011-24730 and SAF2014-57233-R to J.A.E.; SAF2010-15676, SAF2013-43902-R and SAF2015-62540-ERC to S.K.; SAF-2009-09129 to C.V.; SAF2009-12249-C02-01 to F.W.; CSD2010-00045 and SAF2010-14906 to C.G.D.; SAF2013-48812-R to R.P.). The laboratory of S.K. is supported by a grant from Alzheimer’s Association (NIRG-13-279533), from the Basque Ministry of Health (2013111138), from the University of the Basque Country (EHUrOPE14/03) and from Ikerbasque foundation. The laboratory of F.W. is also supported by CIBERNED (an initiative of ISCIII) and by EU-FP7-2009-CT222887 grant. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional Government of Madrid, Botín Foundation, Ramón Areces Foundation, and AXA Foundation. A.M.C. is funded by grants R01CA095063 and R21CA133669 from the US National Institutes of Health. T.W. is funded from the Federal Office for Scientific Affairs (IUAP P6/43) and Flemish Government’s Methusalem Grant. N.Z.G. is funded from the US National Institute on Aging (AG032320), Alzheimer’s Association and American Health Assistance Foundation (AHAF). S.K. was the recipient of a “Ramón y Cajal” contract from the Spanish Ministry of Science and Innovation and is now an IkerBasque Research Professor. C.S.-P. is a recipient of an FPI scholarship from the Spanish Ministry of Economy and Competitiveness (BES-2011-043464). J.M. is the recipient of a predoctoral fellowship (PRE_2014_1_285) from Gobierno Vasco, Departamento de Educación (Basque Country, Spain). Publisher Copyright: © 2016 Nature America, Inc. All rights reserved.

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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U2 - 10.1038/nn.4225

DO - 10.1038/nn.4225

M3 - Article

C2 - 26780512

AN - SCOPUS:84959140220

SN - 1097-6256

VL - 19

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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