Amyloid-beta (Abeta)
peptide aggregation forms such as soluble oligomers (O) have a causal role in neuronal dysfunction and death associated with
Alzheimer?s Disease (AD). The main efforts for the development of
neuroprotective drugs are therefore focused on preventing Abeta production, aggregation or downstream neurotoxic events. We therefore investigated the effect of
guanosine (GUO), a
guanine based
purine, that exerts neurotrophic and
neuroprotective effects. The GUO showed the ability to reduce neuronal death in terms of apoptosis, but not
necrosis, elicited by Abeta1-42O in human
neuroblastoma SH-SY5Y cells. The
neuroprotective effect was recorded only when the GUO was added simultaneously to treatment of the SH-SY5Y cells with Abeta1-42O. By contrast, the GUO treatment of SH-SY5Y cells before and after the appearance of beta1-42O toxicity had no
neuroprotective effects. The employment of specific inhibitors showed the involvement of neuronal survival pathways, such as PI3K?Akt and MAPK-ERK for the GUO anti-apoptotic effects observed. In parallel, the SH-SY5Y cells treated with GUO, in experimental conditions similar to those adopted to evaluate neuronal death, showed a marked decrease of the early
reactive oxygen species formation induced by Abeta1-42O and
pro-oxidant H2O2. In the same neuronal model, GUO was also shown to inhibit the extra- and intra-cellular Abeta1-42 release as well as the
beta-secretase activity evoked by H2O2
pro-oxidant action. Based on these findings, GUO and other
guanine based
purines appear to be a promising class of compounds with neuroprotective properties that may play an important role in the
therapy of AD.