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

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-a͞heme-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 ␤ (A␤) and heme. A␤(1-40) and A␤(1-42) induced a redshift of 15-20 nm in the spectrum of heme-b and heme-a, suggesting that heme binds A␤, 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␤ 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␤, mitochondrial dysfunction, cholesterol, and the proposed efficacy of clioquinol.mitochondria ͉ heme-a ͉ iron ͉ clioquinol ͉ ferrochelatase H eme (ferriprotoporphyrin IX) metabolism appears altered in the brains of Alzheimer's disease (AD) patients. Heme oxygenase (HO) increases in AD (1, 2), and the level of bilirubin (one of the products of heme degradation by HO) is increased in AD patients (3). Mitochondrial complex IV, the only enzyme in cells that contains heme-a (see below) (4), declines in AD (5-8). Heme-a is rate limiting for the assembly of complex IV (9). Furthermore, an inhibitor of muscarinic acetylcholine receptor binding, which increased in AD brain, was suggested to be heme (10, 11). Therefore, we studied heme metabolism in AD brain and nondemented age-matched normal subjects.Heme-b, the product of ferrochelatase (FC) (also known as protoheme), is produced in the mitochondrial matrix (12, 13) and is the precursor for heme-c and heme-a. The structure of heme-c is similar to that of heme-b, but it is covalently attached to a few specific proteins (reviewed in ref. 14). Heme-b and heme-a exist in two major pools in the cell, free and protein-associated. Conversion of heme-b to heme-a requires farnasylation and oxidation (15). Farnesyl-pyrophsphate (FPP) is the precursor for the farnesyl moiety in heme-a, cholesterol, dolichol, farnesylation ...

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

“…Heme has been confirmed to be biosynthesized in brain cells and greatly increased in AD brains [26] . Heme can colocalize with AD senile plaques [27] .…”

“…Recent evidence shows that Aβ can induce intracellular heme synthesis and iron uptake in vitro [9,32] . Heme can bind to Aβ to form heme-Aβ, promoting [24,26,33,34] .…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Although it was initially considered a chelator [198][199][200][201], it has more recently been characterized as a copper/zinc ionophore, which functions to redistribute these metals into cells [196,[202][203][204][205][206]. Clioquinol is still considered a moderate iron chelator as it has been shown to lower iron levels in animal models of iron overload [64,148,[207][208][209][210], and has not been shown to redistribute iron into cells using ionophore assays.…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Finally, Aβ has been proved to bind to heme groups, reducing their bioavailability inside cells and generating a peroxidase enzyme able to oxidize biomolecules (Atamna, 2006;Atamna and Boyle, 2006). This reduction in heme groups would enhance complex IV deficiency since heme-α is essential and rate-limiting for the assembly of this complex (Atamna and Frey, 2004;Atamna and Boyle, 2006). Therefore, increasing evidences point towards a toxic effect of Aβ on mitochondrial function, with a number of mechanisms disturbing complex IV assembly and activity and therefore, RC supercomplexes stability and ROS production.…”