SURVIVAL OF CULTURED NEURONS FROM AMYLOID PRECURSOR PROTEIN KNOCK-OUTMICE AGAINST ALZHEIMERS AMYLOID-BETA TOXICITY AND OXIDATIVE STRESS

Studies on the amyloid precursor protein (APP) have suggested that it may be neuroprotective against amyloid-beta (AP) toxicity and oxidativ e stress. However, these findings have been obtained from either trans fection 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 A beta or oxidative stress has not been determined. This w as investigated using primary cortical and cerebellar neuronal culture s established from APP knock-out (APP(-/-)) and wild-type (APP(+/+)) m ice. Differences in susceptibility to AP 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 a nd 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 A beta-treat ed APP(-/-) and APP(+/+) cultures but not in H2O2-treated cultures. Th is suggests that the AP toxicity pathway differs from other general fo rms of oxidative stress. These findings show that A beta toxicity does not require an interaction of the A beta peptide with the parental mo lecule (APP) and is therefore distinct from prion protein neurotoxicit y that is dependent on the expression of the parental cellular prion p rotein.