Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 30, Pages 11153-11158Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0404349101
Keywords
mitochondria; heme-a; iron; clioquinol; ferrochelatase
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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 is (Abeta) and heme. Abeta((1-40)) and Abeta((1-42)) induced a redshift of 15-20 nm in the spectrum of heme-b and heme-a suggesting that heme binds Abeta, 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 Abeta complexes with free heme, thereby decreasing its bioavailability (e.g., heme-a) and resulting in functional heme deficiency. The model integrates disparate observations, including Abeta, mitochondrial dysfunction, cholesterol, and the proposed efficacy of clioquinol.
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