Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease.
Amyloid precursor protein (APP) generates the beta-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.
Takahashi
M
M
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Doré
S
S
Ferris
C D
CD
Tomita
T
T
Sawa
A
A
Wolosker
H
H
Borchelt
D R
DR
Iwatsubo
T
T
Kim
S H
SH
Thinakaran
G
G
Sisodia
S S
SS
Snyder
S H
SH
D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D001667:Binding, Competitive / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000633:toxicity; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D014162:Transfection; D020798:Two-Hybrid System Techniques
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D007527:Isoenzymes; D008565:Membrane Proteins; D006427:Hemin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2; D001663:Bilirubin