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 journalArticleAcademicpeer-review

26 Citations (Web of Science)

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 languageEnglish
Article number26
Number of pages19
JournalMolecular Neurodegeneration
Volume14
DOIs
Publication statusPublished - 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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