title: Inhibition of heme synthesis alters Amyloid Precursor Protein processing.
abstract: Decay of mitochondria, energy failure and increased oxidative stress are features commonly detected in brains from Alzheimer's disease (AD) patients. Recent findings indicate that neuronal heme deficiency may contribute to the appearance of those cytopathologies and potentially alter the course of AD. We repressed heme synthesis in cells by inhibiting ferrochelatase enzyme with small interfering RNA and N-methylprotoporphyrin IX. The treatments induced a severe perturbation of mitochondria and energy production, with decrease of the subunit II of Cytochrome c Oxidase, alteration of the membrane potential and a 50% reduction of intracellular ATP. The state and processing of the Amyloid Precursor Protein (APP) was also affected, with the appearance of APP aggregates and a significant decrease (30-40%) of sAPPalpha secretion, associated with perturbation of ADAM10 and TACE, enzymes involved in the alpha-secretase cleavage. The production of sAPPbeta was increased, without augment of Amyloid beta generation. Our findings strengthen the hypothesis that a reduced availability of heme may play a role in AD pathogenesis.
authors.affiliation: Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, viale Europa 11, 25123, Brescia, Italy.
authors.forename: Luisa Benerini
authors.initials: LB
authors.lastname: Gatta
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Vitali
authors.forename: Rosanna
authors.initials: R
authors.lastname: Verardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000255:Adenosine Triphosphate / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005294:Ferrochelatase / Q000037:antagonists & inhibitors / Q000235:genetics; D006418:Heme / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism; D010829:Physiological Phenomena / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010446:Peptide Fragments; D011524:Protoporphyrins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C078592:amyloid beta-protein (1-40); D006418:Heme; C028842:N-methylprotoporphyrin IX; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D005294:Ferrochelatase