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The Journal of Neuroscience, August 15, 1998, 18(16):6207-6217

Survival of Cultured Neurons from Amyloid Precursor Protein Knock-Out Mice against Alzheimer's Amyloid- Toxicity and Oxidative Stress

Anthony R. White¹, Hui Zheng², Denise Galatis¹, Fran Maher¹, Lars Hesse³, Gerd Multhaup³, Konrad Beyreuther³, Colin L. Masters¹, and Roberto Cappai¹

¹ Department of Pathology, The University of Melbourne and The Mental Health Research Institute, Parkville, Victoria, Australia, 3052, ² Department of Genetics and Molecular Biology, Merck Research Laboratories, Rahway, New Jersey 07065, and ³ Center of Molecular Biology, The University of Heidelberg, 69120 Heidelberg, Germany

Studies on the amyloid precursor protein (APP) have suggested that it may be neuroprotective against amyloid- (A) 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 A 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 A 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 A-treated APP^/ and APP^+/+ cultures but not in H₂O₂-treated cultures. This suggests that the A toxicity pathway differs from other general forms of oxidative stress. These findings show that A toxicity does not require an interaction of the A 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.

Key words: A25-35; cortical neurons; neurotoxicity; APP; Alzheimer's disease; knock-out mice

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18166207-11$05.00/0

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