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 sAPPα secretion, associated with perturbation of ADAM10 and TACE, enzymes involved in the α-secretase cleavage. The production of sAPPβ was increased, without augment of Amyloid β generation. Our findings strengthen the hypothesis that a reduced availability of heme may play a role in AD pathogenesis.