Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease

Amyloid precursor protein (APP) generates the beta -amyloid peptide, postul ated to participate in the neurotoxicity of Alzheimer's disease. We report that APP and APLP bind to heme oxygenase (HO), an enzyme whose product, bil irubin, is antioxidant and neuroprotective. The binding of APP inhibits HO activity, and APP with mutations linked to the familiar Alzheimer's disease (FAD) provides substantially greater inhibition of HO activity than wild-t ype APP. Cortical cultures from transgenic mice expressing Swedish mutant A PP have greatly reduced bilirubin levels, establishing that mutant APP inhi bits HO activity in vivo. Oxidative neurotoxicity is markedly greater in ce rebral cortical cultures from APP Swedish mutant transgenic mice than wild- type cultures. These findings indicate that augmented neurotoxicity caused by APP-HO interactions may contribute to neuronal cell death in Alzheimer's disease.