The toxic effects of human Aβ42 peptide on synapses can be prevented by PI3K activation. This neuroprotection is achieved by increasing the insoluble aggregates of the peptide through the PI3K-triggered phosphorylation of the Ser-26 residue in Aβ42. The Aβ42 toxicity syndrome includes the abrogation of PI3K expression.
Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer’s disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer’s disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.
Alzheimer's disease is, to a large extent, a disease of the synapse triggered by the unbalanced amyloidogenic cleavage of the amyloid precursor protein APP. Excess of Aβ42 peptide in particular is considered a hallmark of the disease. Here we drive the expression of the human Aβ42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. We show that the neuronal expression of the human peptide elicits progressive toxicity in the adult. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as life-span reduction. The Aβ42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes: bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the co-expression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and Thioflavin-positive amyloid deposits. Mechanistically, we suggest that Aβ42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Finally, along with these in vivo experiments we further analyze Aβ42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where Aβ42 aggregation into large insoluble deposits is reproduced. Taken together, these results uncover a potential novel pharmacological strategy against this disease with PI3K activation as a target.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.