AIM The amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (Aβ) or the secreted ectodomain APP alpha (sAPPα). While neurotrophic properties of sAPPα were suggested in several studies, it is still unclear if and how sAPPα counteracts pathogenic effects of Aβ. Direct comparisons with sAPPβ, produced in the Aβ-generating pathway, are missing in order to determine the role of sAPPα's carbonyl-terminal end in its possible neuroprotective activity. METHODS Mouse neuronal primary cultures and hippocampal slices were treated with oligomeric Aβ. The effects on tau phosphorylation and dendritic spine densities were assessed by western blot and confocal imaging, respectively. Co-administration of either sAPPα or sAPPβ was used to determine activity on Aβ-induced toxicity. RESULTS/DISCUSSION We found that oligomeric Aβ strongly increased AT8 and AT180 phosphorylation of tau and caused a loss of dendritic spines. SAPPα completely abolished Aβ effects whereas sAPPβ had no such rescue activity. Interestingly, sAPPα or sAPPβ alone neither affected tau phosphorylation nor dendritic spine numbers. Together, our data suggest that sAPPα specifically protects neurons against Aβ-dependent toxicity supporting the strategy of activating α-secretase-dependent endoproteolytic APP processing to increase sAPPα shedding from the neuronal plasma membrane as a therapeutic intervention for the protection of dendritic spines and phospho-tau-dependent toxicity in Alzheimer's disease.