A role for heme in Alzheimer's disease: heme binds amyloid beta and has altered metabolism.
Heme is a common factor linking several metabolic perturbations in Alzheimer's disease (AD), including iron metabolism, mitochondrial complex IV, heme oxygenase, and bilirubin. Therefore, we determined whether heme metabolism was altered in temporal lobes obtained at autopsy from AD patients and age-matched nondemented subjects. AD brain demonstrated 2.5-fold more heme-b (P < 0.01) and 26% less heme-a (P = 0.16) compared with controls, resulting in a highly significant 2.9-fold decrease in heme-a/heme-b ratio (P < 0.001). Moreover, the strong Pearson correlation between heme-a and heme-b measured in control individuals (r(2) = 0.66, P < 0.002, n = 11) was abolished in AD subjects (r(2) = 0.076, P = 0.39, n = 12). The level of ferrochelatase (which makes heme-b in the mitochondrial matrix) in AD subjects was 4.2 times (P < 0.04) that in nondemented controls, suggesting up-regulated heme synthesis. To look for a possible connection between these observations and established mechanisms in AD pathology, we examined possible interactions between amyloid beta (A beta) and heme. A beta((1-40)) and A beta((1-42)) induced a redshift of 15-20 nm in the spectrum of heme-b and heme-a, suggesting that heme binds A beta, likely to one or more of the histidine residues. Lastly, in a tissue culture model, we found that clioquinol, a metal chelator in clinical trials for AD therapy, decreased intracellular heme. In light of these observations, we have proposed a model of AD pathobiology in which intracellular A beta complexes with free heme, thereby decreasing its bioavailability (e.g., heme-a) and resulting in functional heme deficiency. The model integrates disparate observations, including A beta, mitochondrial dysfunction, cholesterol, and the proposed efficacy of clioquinol.
Atamna
Hani
H
Nutritional Genomics Center, Children's Hospital Oakland Research Institute, CA 94609, USA. hatamna@chori.org
Frey
William H
WH
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000378:metabolism; D006418:Heme / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D012016:Reference Values; D013702:Temporal Lobe / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D006418:Heme; D003300:Copper; D015032:Zinc