Studies on the amyloid precursor protein (APP) have suggested that it may be neuroprotective against amyloid-β (Aβ) toxicity and oxidative stress. However, these findings have been obtained from either transfection of cell lines and mice that overexpress human APP isoforms or pretreatment of APP-expressing primary neurons with exogenous soluble APP. The neuroprotective role of endogenously expressed APP in neurons exposed to Aβ or oxidative stress has not been determined. This was investigated using primary cortical and cerebellar neuronal cultures established from APP knock-out (APP^−/−) and wild-type (APP^+/+) mice. Differences in susceptibility to Aβ toxicity or oxidative stress were not found between APP^−/− and APP^+/+ neurons. This observation may reflect the expression of the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2) molecules and supports the theory that APP and the APLPs may have similar functional activities. Increased expression of cell-associated APLP2, but not APLP1, was detected in Aβ-treated APP^−/− and APP^+/+ cultures but not in H₂O₂-treated cultures. This suggests that the Aβ toxicity pathway differs from other general forms of oxidative stress. These findings show that Aβ toxicity does not require an interaction of the Aβ peptide with the parental molecule (APP) and is therefore distinct from prion protein neurotoxicity that is dependent on the expression of the parental cellular prion protein.