Inhibition of heme synthesis alters Amyloid Precursor Protein processing.
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.
Gatta
Luisa Benerini
LB
Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, viale Europa 11, 25123, Brescia, Italy.
Vitali
Massimiliano
M
Verardi
Rosanna
R
Arosio
Paolo
P
Finazzi
Dario
D
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
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