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

Masaaki Takahashi, Sylvain Doré, Christopher D. Ferris, Taisuke Tomita, Akira Sawa, Herman Wolosker, David R. Borchelt, Takeshi Iwatsubo, Seong Hun Kim, Gopal Thinakaran, Sangram S. Sisodia, Solomon H. Snyder

Research output: Contribution to journalArticle

Abstract

Amyloid precursor protein (APP) generates the β-amyloid peptide, postulated to participate in the neurotoxicity of Alzheimer's disease. We report that APP and APLP bind to heme oxygenase (HO), an enzyme whose product, bilirubin, is antioxidant and neuroprotective. The binding of APP inhibits HO activity, and APP with mutations linked to the familial Alzheimer's disease (FAD) provides substantially greater inhibition of HO activity than wild-type APP. Cortical cultures from transgenic mice expressing Swedish mutant APP have greatly reduced bilirubin levels, establishing that mutant APP inhibits HO activity in vivo. Oxidative neurotoxicity is markedly greater in cerebral 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.

Original languageEnglish (US)
Pages (from-to)461-473
Number of pages13
JournalNeuron
Volume28
Issue number2
DOIs
StatePublished - Jan 1 2000

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Takahashi, M., Doré, S., Ferris, C. D., Tomita, T., Sawa, A., Wolosker, H., Borchelt, D. R., Iwatsubo, T., Kim, S. H., Thinakaran, G., Sisodia, S. S., & Snyder, S. H. (2000). Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease. Neuron, 28(2), 461-473. https://doi.org/10.1016/S0896-6273(00)00125-2