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Review
. 2010 Nov;14(11):1177-97.
doi: 10.1517/14728222.2010.525352.

Novel drug targets based on metallobiology of Alzheimer's disease

Sanghamitra Bandyopadhyay  1 , Xudong Huang, Debomoy K Lahiri, Jack T Rogers
Affiliations
Review

Novel drug targets based on metallobiology of Alzheimer's disease

Sanghamitra Bandyopadhyay et al. Expert Opin Ther Targets. 2010 Nov.

Abstract

Importance of the field: Increased localization of Zn, Fe, Cu and Al within the senile plaques (SP) exacerbates amyloid beta (Aβ)-mediated oxidative damage, and acts as catalyst for Aβ aggregation in Alzheimer's disease (AD). Thus, disruption of aberrant metal-peptide interactions via chelation therapy holds considerable promise as a rational therapeutic strategy against Alzheimer's amyloid pathogenesis.

Areas covered in this review: The complexities of metal-induced genesis of SP are reviewed. The recent advances in the molecular mechanism of action of metal chelating agents are discussed with critical assessment of their potential to become drugs.

What the reader will gain: Taking into consideration the interaction of metals with the metal-responsive elements on the Alzheimer's amyloid precursor protein (APP), readers will gain understanding of several points to bear in mind when developing a screening campaign for AD-therapeutics.

Take home message: A functional iron-responsive element (IRE) RNA stem loop in the 5' untranslated region (UTR) of the APP transcript regulates neural APP translation. Desferrioxamine, clioquinol, tetrathiolmolybdate, dimercaptopropanol, VK-28, and natural antioxidants, such as curcumin and ginko biloba need critical evaluation as AD therapeutics. There is a necessity for novel screens (related to metallobiology) to identify therapeutics effective in AD.

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Conflict of interest statement

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Figures

Figure 1.
Figure 1.. Synchrotron X-ray fluorescence (XRF) microprobe images of human Alheimer’s disease AD plaque.
Elemental profiles (S, Fe, Cu, and Zn) in a typical Alzheimer’s amyloid beta (Aβ) amyloid plaque. The cryo-sectioned (10 μm thickness) AD brain tissues were stained with 0.1% Thioflavin-T for amyloid plaques. The amyloid plaque-bearing human brain tissues were procured by laser capture microdissection (LCM) (Arcturus Pixcell IIE platform) and mounted on Si3N4 membrane grids (2.0 × 2.0 mm). Guided by the optical amyloid plaque images, the samples were excited with incident synchrotron X-ray of 10 keV for elemental Kα characteristic emission lines. Elemental profiles (S, Fe, Cu, and Zn) were obtained using synchrotron scanning X-ray fluorescence microscopy (μ-XRF) at the Advanced Photon Source of the Argonne National Laboratory. Red depicts the hottest spot of the metals in plaques. (The significance of sulfur (S) element may reflect its high abundance in proteinaceous elemental composition and as an indicator for amyloid plaque-associated oxidative stress since protein S-glutathionylation is a salient feature of oxidative stress). Reproduced from [7].
Figure 2.
Figure 2.. The proteolytic processing of amyloid precursor protein (APP) to produce Aβ that coordinates the metal ions (M: Zn, Cu and Fe) to induce aggregation, and generation of ROS.
APP (695, 751, 770 amino acid isoforms that predominate in brain) can be processed in the plasma membrane as it travels from the intracellular origin to extracellular matrix through the non-amyloidogenic route that involves cleavage at the α-secretase site at amino acid 17 of the 40 – 42 amino acid Aβ domain resulting in two fragments, sAPPα and a C-terminal fragment (CTFα). Further proteolysis of the CTFα fragment by α-secretase generates the non-amyloidogenic peptide p3 and a C-terminal fragment CTFγ. When APP escapes processing at the α-site, it undergoes β-secretase cleavage at the beginning of Aβ domain, resulting in a C-terminal fragment CTFβ and sAPPβ. Next, the resultant β-stub becomes the substrate for γ-secretase cleavage, culminating in extracellular Aβ secretion. The hyper-metallated (by Zn, Fe and Cu) state of Aβ as a consequence of age-dependent elevations in tissue metal concentrations can induce Aβ aggregation. H2O2 can initiate a number of oxidative events, including Fenton reactions to form toxic hydroxyl radicals and calcium dysregulation, and subsequent reactive oxygen species (ROS) generation.
Figure 3.
Figure 3.. Model for the iron-induced change of iron regulatory protein (IRP) interaction with the APP/ferritin iron-responsive element (IRE) to modulate APP/ferritin translation.
The APP IRE is homologous with the canonical L-and H-ferritin IRE mRNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2), and modulates translation of ferritin to control intracellular iron homoeostasis [226]. Iron influx increases ferritin mRNA translation by releasing IRP1–IRP2 binding to the 5′ cap site of IRE stem–loop. The iron-induced change of IRP1 interaction with the APP-IRE activates either 5′cap translation or internal 40S ribosome entry and the onset of APP protein synthesis [227]. The IRE of APP interacts with IRP1, whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, in human brain cortex tissue and human blood lysates. The canonical H-ferritin IRE RNA stem-loop binds also to IRP2. The APP mRNA acute box domain, as for H-ferritin mRNA, is located immediately upstream of the start codon and may well also interact with RNA poly(C)-binding proteins, CP-1 and CP-2 and control cytokine-induced APP mRNA translation.
Figure 4.
Figure 4.. Important metal-chelators characterized as suppressors of APP and Aβ aggregation.
Chemical structures of A. Clioquinol, which inhibits Zn, Cu- or Fe-mediated oxidative stress and reduces clinically observed AD-induced cognition; B. Desferrioxamine, intracellular Fe3+ chelator that suppresses APP translation without changing α-secretase activity; C & D M-30 and VK-28. M-30 being derived from a prototype iron chelator, VK-28; both being developed for anti-amyloid efficacy and α-secreatase co-activation; E. Bifunctional XH1: [(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-{2-[(2-{[(4-benzothiazol-2-yl-phenylcarbamoyl)methyl]-carboxymethyl-amino}-ethyl)-carboxymethyl-amino]-ethyl}-amino)-acetic acid, with amyloidtargeting metal chelating property; F. Tetrathiomolybdate, which shows excellent efficacy in animal AD models and is presently under clinical trial. G. Dimercaptopropanol, which has a significant effect on Aβ metabolism in vitro and/or in vivo.
Figure 5.
Figure 5.. Metallo-complexes that target neuronal signaling.
Chemical structures of A. Cu-bis(thiosemicarbazone) that reduces tau phosphorylation through PI3K and ras/raf signalling; B. Lipoic acid that chelates metal ion and promotes pro-survival signaling pathways.
Figure 6.
Figure 6.. Proposed metal ligand action that targets neuronal cell signaling in treatment of AD.
Metal-free ligands (L) such as CQ or PBT2 may bind with Cu of the Aβ peptide-Cu complex resulting in dissolution of Aβ into Cu-free monomers. The metal ligand–Cu complexes or alternative metal complexes such as Cu-bis(thiosemicarbazone) then enter cells, activate PI3K followed by sequential phosphorylation of AKT and glycogen synthase kinase beta (GSK3β) that inhibits tau phosphorylation [228]. The complex-mediated activation of ras/raf signalling activates ERK, upregulates MMP activity, which cleaves the monomeric Aβ. Adapted from [90].
Figure 7.
Figure 7.. Important metal-chelators characterized as natural antioxdants for AD.
Chemical structures of A. curcumin, a polyphenol that binds Fe and Cu on Aβ and prevents amyloid aggregation; B. Ginko biloba, inhibits a free radical scavenger that reduces clinically observed AD-induced cognition; C. (−)-epigallocatechin-3-gallate (EGCG) decreased Aβ levels and plaques via promotion of α-secretase activity.
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