Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by Up-regulation of the Nitric Oxide Cascade.

Background: Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory, therefore representing a critical hallmark in the etiopathogenesis of Alzheimer’s disease. However, the molecular mechanisms underlying the Synaptic and memory dysfunction induced by elevation of oTau are still unknown. Methods: Using a combination of biochemical, electrophysiological and behavioral techniques, phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, as well as long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation, and both short-term spatial and associative memory, were examined following oTau elevation with/out up-regulating the nitric oxide (NO) cascade. Results: Phospho-CREB increase occurring during memory formation was found to be reduced after oTau elevation during memory formation. This lead us to explore whether upregulation of various components of the NO signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of synaptic plasticity, memory and CREB phosphorylation. Increased NO levels protected against oTau-induced impairment of LTP. This beneficial effect involved the activation of soluble guanylyl cyclase and elevation of cGMP levels, which stimulate cGMP-dependent protein kinases (PKG). Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 rescued oTau-induced LTP reduction. Activation of PKG rescued oTau-induced LTP and memory impairments. Finally, elevation of cGMP levels re-established normal CREB phosphorylation after LTP 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