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Comparative Study
. 2004 Jul 27;101(30):11153-8.
doi: 10.1073/pnas.0404349101. Epub 2004 Jul 19.

A role for heme in Alzheimer's disease: heme binds amyloid beta and has altered metabolism

Hani Atamna  1 , William H Frey 2nd
Affiliations
Comparative Study

A role for heme in Alzheimer's disease: heme binds amyloid beta and has altered metabolism

Hani Atamna et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Levels of heme-b and heme-a in the temporal lobe of nondemented control and AD subjects. In the temporal lobe from AD patients, heme-b increased 2.5-fold, whereas heme-a shows a moderate decline of 26% (did not reach significance). Heme-b and heme-a were determined as described in Materials and Methods. Data for heme-b are mean ± SEM (nonparametric Mann–Whitney test, P < 0.01, n = 11 for control and n = 12 for AD subjects). Data are for heme-a are mean ± SEM (P = 0.16 Student's t test, n = 11 and 12 for control and AD subjects, respectively).
Fig. 2.
Fig. 2.
The ratio heme-a/heme-b ratio in the temporal lobe of nondemented control and AD subjects. In the temporal lobe of AD patients the ratio heme-a/heme-b ratio decreased 2.9-fold compared with controls. The ratio heme-a/heme-b ratio was calculated from the data in Fig. 1. Data are mean ± SEM (nonparametric Mann–Whitney test, P < 0.001, n = 11 and 12 for control and AD subjects, rspectively).
Fig. 3.
Fig. 3.
Levels of FC in the temporal lobe of nondemented control and AD subjects. Levels of FC increased in the temporal lobe in most of the AD subjects. A representative Western blot analysis for FC is shown. Numbers on the gel refer to coding of subjects. Protein density in FC band in the gel from AD and age-matched control subjects on average were 70,080 ± 23,310 and 16,820 ± 8,017 (n = 10, P < 0.04), respectively (mean ± SEM, nonparametric Mann–Whitney test, P < 0.04, n = 11 and 12 for control and AD subjects, respectively). FC determination was as described in Materials and Methods.
Fig. 4.
Fig. 4.
Correlative analysis of heme-a vs. heme-b in the temporal lobe of nondemented control and AD subjects. A strong Pearson correlation between heme-a and heme-b in control (A) was abolished in AD (B) subjects. (A) A significant positive correlation between heme-a and heme-b is seen in the temporal lobe of normal subjects (P < 0.002, r2 = 0.66, n = 11). (B) The correlation between heme-a and heme-b in the temporal lobe of AD subjects was not significant (P < 0.39, r2 = 0.076, n = 12).
Fig. 5.
Fig. 5.
Clioquinol decreases heme in normal human fibroblasts (IMR90) and in human astrocytoma (U373) cells. Clioquinol (Cq) lowers heme in IMR90 and U373 cells. The cells were incubated with 10 μM Cq for a week. Heme was analyzed as described in Materials and Methods. One representative experiment of each cell type is shown (U373, Student's t test, P < 0.005; IMR90, Student's paired t test, P < 0.006). Con, control.
Fig. 6.
Fig. 6.
Spectral redshift to heme induced by Aβ.Aβ(1–40) or Aβ(1–42) induces a redshift of 18 and 15 nm in heme-b and heme-a, respectively. The spectral change of heme-b (A) or heme-a (B) induced by Aβ were determined as described in Materials and Methods.Aβ was used at a final concentration of 50 μM. The concentration of heme-b was 50 μM and 30 μM for heme-a. All chemicals were mixed in 50 mM Hepes (pH 7), and spectra were collected immediately at room temperature by using a SpectraMAX 340 plate reader.
Scheme 1.
Scheme 1.
Possible metabolic consequences of heme-binding Aβ. Intracellular Aβ aggregation may be prevented by binding to free heme-b and heme-a, although a decline in their free pools could be a possible side effect. Increased cholesterolgenesis may compete with heme-a maturation on FPP (27), causing even more decrease in heme-a. Low heme-a limits assembly of complex IV and causes up-regulation of heme-b synthesis. If the rate of production of Aβ exceeds the capacity of heme synthesis or there is an increase in free metals, then excess Aβ reacts with free metals and forms aggregates (see Discussion). The Km values for FPP in FPP-dependent metabolic pathways are in parentheses.?, Km not determined; ↑, increased rate of production of Aβ; *, pathways not demonstrated in vivo.
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