Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Erica Acquarone; Elentina K. Argyrousi; Manon van den Berg; Walter Gulisano; Mauro Fa; Agnieszka Staniszewski; Elisa Calcagno; Elisa Zuccarello; Luciano D'Adamio; Shi-Xian Deng; Daniela Puzzo; Ottavio Arancio; Jole Fiorito

doi:10.1186/s13024-019-0326-4

Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Walter Gulisano, Mauro Fa, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Luciano D'Adamio, Shi-Xian Deng, Daniela Puzzo, Ottavio Arancio^*, Jole Fiorito^*

^*Corresponding author for this work

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

Abstract

Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.

Methods: This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation.

Results: Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau.

Conclusions: Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

Original language	English
Article number	26
Number of pages	19
Journal	Molecular Neurodegeneration
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13024-019-0326-4
Publication status	Published - 27 Jun 2019

Keywords

Tau oligomers
Nitric oxide
Soluble guanylyl cyclase
PDE5
Protein kinase G
CREB
Memory
Alzheimer's disease
DEPENDENT PROTEIN-KINASE
LONG-TERM POTENTIATION
ELEMENT-BINDING PROTEIN
PHOSPHODIESTERASE 5 INHIBITOR
PAIRED HELICAL FILAMENTS
SELECTIVE PDE5 INHIBITOR
ALZHEIMERS-DISEASE
OBJECT MEMORY
MOUSE MODEL
ADENYLYL-CYCLASE

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1 Erratum / corrigendum / retractions

Correction: Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade (Vol 14, 26, 2019)
Acquarone, E., Argyrousi, E. K., van den Berg, M., Gulisano, W., Fa, M., Staniszewski, A., Calcagno, E., Zuccarello, E., D'Adamio, L., Deng, S.-X., Puzzo, D., Arancio, O. & Fiorito, J., 29 Apr 2024, In: Molecular Neurodegeneration. 19, 1, 2 p., 39.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

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Acquarone, E., Argyrousi, E. K., van den Berg, M., Gulisano, W., Fa, M., Staniszewski, A., Calcagno, E., Zuccarello, E., D'Adamio, L., Deng, S.-X., Puzzo, D., Arancio, O., & Fiorito, J. (2019). Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade. Molecular Neurodegeneration, 14(1), Article 26. https://doi.org/10.1186/s13024-019-0326-4

@article{04d6175c56ff4f998d068b36f4284ee8,

title = "Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade",

abstract = "Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.Methods: This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation.Results: Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau.Conclusions: Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.",

keywords = "Tau oligomers, Nitric oxide, Soluble guanylyl cyclase, PDE5, Protein kinase G, CREB, Memory, Alzheimer's disease, DEPENDENT PROTEIN-KINASE, LONG-TERM POTENTIATION, ELEMENT-BINDING PROTEIN, PHOSPHODIESTERASE 5 INHIBITOR, PAIRED HELICAL FILAMENTS, SELECTIVE PDE5 INHIBITOR, ALZHEIMERS-DISEASE, OBJECT MEMORY, MOUSE MODEL, ADENYLYL-CYCLASE",

author = "Erica Acquarone and Argyrousi, {Elentina K.} and {van den Berg}, Manon and Walter Gulisano and Mauro Fa and Agnieszka Staniszewski and Elisa Calcagno and Elisa Zuccarello and Luciano D'Adamio and Shi-Xian Deng and Daniela Puzzo and Ottavio Arancio and Jole Fiorito",

note = "Funding Information: Work on this manuscript was supported by NIH grant R01AG049402 to OA and Alzheimer{\textquoteright}s Association grant AARF-17-504483 to JF. Funding Information: OA is a founder of Neurokine Therapeutics. OA has received research funding from Appia Pharmaceuticals LLC. EA, EKA, MVdB, WG, MF, AS, EC, EZ, LD, SXD, PD, and JF declare that they have no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = jun,

day = "27",

doi = "10.1186/s13024-019-0326-4",

language = "English",

volume = "14",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central Ltd",

number = "1",

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Acquarone, E, Argyrousi, EK, van den Berg, M, Gulisano, W, Fa, M, Staniszewski, A, Calcagno, E, Zuccarello, E, D'Adamio, L, Deng, S-X, Puzzo, D, Arancio, O & Fiorito, J 2019, 'Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade', Molecular Neurodegeneration, vol. 14, no. 1, 26. https://doi.org/10.1186/s13024-019-0326-4

TY - JOUR

T1 - Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

AU - Acquarone, Erica

AU - Argyrousi, Elentina K.

AU - van den Berg, Manon

AU - Gulisano, Walter

AU - Fa, Mauro

AU - Staniszewski, Agnieszka

AU - Calcagno, Elisa

AU - Zuccarello, Elisa

AU - D'Adamio, Luciano

AU - Deng, Shi-Xian

AU - Puzzo, Daniela

AU - Arancio, Ottavio

AU - Fiorito, Jole

N1 - Funding Information: Work on this manuscript was supported by NIH grant R01AG049402 to OA and Alzheimer’s Association grant AARF-17-504483 to JF. Funding Information: OA is a founder of Neurokine Therapeutics. OA has received research funding from Appia Pharmaceuticals LLC. EA, EKA, MVdB, WG, MF, AS, EC, EZ, LD, SXD, PD, and JF declare that they have no competing interests. Publisher Copyright: © 2019 The Author(s).

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.Methods: This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation.Results: Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau.Conclusions: Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

AB - Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.Methods: This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation.Results: Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau.Conclusions: Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

KW - Tau oligomers

KW - Nitric oxide

KW - Soluble guanylyl cyclase

KW - PDE5

KW - Protein kinase G

KW - CREB

KW - Memory

KW - Alzheimer's disease

KW - DEPENDENT PROTEIN-KINASE

KW - LONG-TERM POTENTIATION

KW - ELEMENT-BINDING PROTEIN

KW - PHOSPHODIESTERASE 5 INHIBITOR

KW - PAIRED HELICAL FILAMENTS

KW - SELECTIVE PDE5 INHIBITOR

KW - ALZHEIMERS-DISEASE

KW - OBJECT MEMORY

KW - MOUSE MODEL

KW - ADENYLYL-CYCLASE

U2 - 10.1186/s13024-019-0326-4

DO - 10.1186/s13024-019-0326-4

M3 - Article

C2 - 31248451

SN - 1750-1326

VL - 14

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

IS - 1

M1 - 26

ER -

Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Abstract

Keywords

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Research output

Correction: Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade (Vol 14, 26, 2019)

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