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

Erica Acquarone,Elisa Zuccarello,Walter Gulisano,Daniela Puzzo,Elentina K Argyrousi,Ottavio Arancio,Manon Van Den Berg,Luciano D’Adamio,Mauro Fà,Elisa Calcagno,Agnieszka Staniszewski,Jole Fiorito,Shi-Xian Deng

doi:10.1186/s13024-019-0326-4

Abstract

BackgroundSoluble 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.MethodsThis 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.ResultsLevels 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.ConclusionsUp-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

Highlights

Soluble aggregates of oligomeric forms of tau protein have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease
Results oTau affects molecular mechanisms underlying memory formation Considering the profound effect that oTau exposure has on synaptic plasticity and memory [1, 2], we decided to determine whether the molecular mechanisms underlying memory formation, including cyclic adenosine monophosphate (cAMP)-responsive element binding (CREB) phosphorylation, are affected by oTau
We detected a slight increase in acetylation of the chromatin-associated protein histone 3 (H3) at the lysine residue 27, 1 min after the shock, which became significant at 60 min, as well as in the expression of the immediate early gene Arc that is implicated in memory formation, both at 1 and 60 min after the shock (Fig. 1d-e)

Summary

Introduction

Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease. CREB is at the crossroads of several molecular pathways and mechanisms that have been proposed as potential therapeutic targets against AD, including the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) dependent protein kinases (PKG)/CREB pathway, the cAMP-dependent protein kinases (PKA)/CREB pathway and the mitogenactivated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway [16]. To this regard, the NO/ cGMP/PKG/CREB cascade is attractive because drugs boosting it, especially phosphodiesterase 5 (PDE5) inhibitors, are widely used for the therapy of erectile dysfunction and pulmonary hypertension [24], and it is plausible that their administration is compatible with therapeutic usage

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