Metal compounds as inhibitors of β-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer's disease

doi:10.1016/j.ccr.2012.04.010

Coordination Chemistry Reviews

Volume 256, Issues 19–20, October 2012, Pages 2357-2366

https://doi.org/10.1016/j.ccr.2012.04.010 Get rights and content

Abstract

Alzheimer's disease (AD) is a widespread neurodegenerative disease with a very high medical, social and economic burden. The etiopathogenesis of AD is still largely obscure; however, there is growing evidence that aggregation of β-amyloid peptides (Aβ) into a variety of supramolecular structures is critically involved in its insurgence and progression (the so called “amyloid cascade hypothesis”). Recent results point to oligomeric Aβ aggregates rather than mature Aβ fibrils as the major culprit for neurotoxicity; details of the inherent aggregation processes are being progressively clarified. In view of these achievements, early stages of Aβ aggregation are considered today a realistic “druggable” target for the development of new anti-AD agents. Notably, a variety of organic compounds that are able to inhibit effectively Aβ aggregation represent promising drug candidates. Metal based compounds capable of interacting with the N-terminal metal binding site of amyloid peptides might similarly contrast metal-induced Aβ aggregation and serve as potential drugs for AD. In a recent pioneering study Barnham et al. showed that platinum(II) phenanthroline complexes strongly inhibit Aβ oligomerisation and attenuate its neurotoxicity in vitro. A number of additional examples involving metal complexes as inhibitors of Aβ aggregation were reported afterward. On the ground of those results it may be proposed that metal based compounds constitute today a suitable and rich source for novel anti-AD agents. The potential and the limits of this therapeutic option are comprehensively and critically discussed as well as the perspectives for future research.

Highlights

► Aggregation of β-amyloid peptides into “soluble oligomers” constitutes a realistic druggable target for AD. ► A number of late transition metal compounds – e.g. Pt and Ru – manifest high affinity for the metal binding site of Aβ peptides and drastically alter their aggregation behaviour. ► Metal binding greatly decreases neurotoxicity in vitro of Aβ peptides. ► Metal based compounds represent promising agents for an innovative therapeutic of AD.

Section snippets

Alzheimer's disease: some general remarks

Alzheimer's disease (AD), is nowadays the most common cause of dementia in adults; it is associated with selective damage of a few brain regions and neural circuits that are critical for memory and cognition. Presently, there is no cure for this disease that worsens progressively and eventually leads to death within a few years. AD was first described by the German neuropathologist Alois Alzheimer in 1906 and named after him [1]. In most cases, it is diagnosed in people over 65 although a

Etiopathogenesis of Alzheimer's disease: the “amyloid cascade hypothesis”

The brains of people with AD show an abundance of two abnormal structures i.e. β-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells, and neurofibrillary tangles, which are twisted fibers, mainly containing tau protein, that build up inside the nerve cell. Formation of amyloid plaques and of neurofibrillary tangles are commonly considered the two major histopathological hallmarks of AD [10], [11].

The so called “amyloid

Molecular aspects of amyloid peptides and of their aggregation

A number of molecular aspects of the “amyloid cascade hypothesis” were investigated and disclosed during the last few years, inspiring the scientific community for developing new types of AD therapeutics. In particular, research has focused on the structural characterisation of the amyloid peptides, either in monomeric or in aggregate form.

Monomeric Aβ₄₀ and Aβ₄₂ are intrinsically unstructured, implying that in solution they do not assume any compact tertiary fold but rather populate a large

Blocking Aβ amyloid aggregation as a strategy to contrast AD

Structural insights into the conformational modifications associated with Aβ aggregation and with assembly of amyloid fibrils suggested a variety of potential targets for therapeutic intervention. As mentioned above, solid-state NMR, hydrogen/deuterium exchange and mutagenesis strategies were exploited to probe the secondary and tertiary structure of amyloid fibrils and of some key intermediates. Accordingly, a rational design of peptide inhibitors was made possible directed against residues

Metal based compounds as tools for blocking amyloid aggregation

Molecular studies on Aβ peptides, and specifically on the most important of them, i.e. Aβ₄₂ and Aβ₄₀, showed that these peptides contain a portion rich in histidines close to their N-terminus which manifests significant metal binding properties. Based on this observation, copper, iron and zinc ions were postulated to bind β amyloid peptides under physiological conditions and to influence greatly their aggregation and pathogenicity. In particular, these metals may affect the rate of aggregation

Advantages and disadvantages in the use of metal based compounds as experimental anti-AD agents

Metal based drugs form today an important class of pharmaceutical agents with a large variety of therapeutic indications. Their use as anticancer agents is now firmly established owing to the primary role played by platinum drugs in several chemotherapeutic regimens; however, many other therapeutic applications of metal based drugs were reported such as antiarthritic, antimaniacal and antiulcer agents. At the same time, it must be reminded that metal based drugs have been explored far less

Conclusions and perspectives

The field of metal based drugs is a rapidly growing one. Indeed, the rich and versatile chemistry of the various metal centers may be specifically exploited for numerous therapeutic applications. Notably, recent studies revealed that some late transition metal compounds may be successfully administered in vitro to block beta amyloid aggregation and reduce its inherent neurotoxicity. This type of pharmacological approach looks very attractive as it takes advantage of the presence of a high

Acknowledgment

We thank the Ministry of Education, University and Research (MIUR)–PRIN grant 2008, for financial support.

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Citation Excerpt :
These strategies for developing appropriate remedy include employment of small molecules/drugs, polyphenols, anthraquinones, flavonoids, vitamins and nanoparticles etc. [6,7]. Previous studies have suggested that metal ions could also inhibit β-amyloid formation [8]. Binding of nanoparticles as well as small molecules like inorganic phosphates to the polypeptide can also prevent its aggregation by stabilizing the polypeptide [9,10].
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ReviewMetal compounds as inhibitors of β-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer's disease

Abstract

Highlights

Section snippets

Alzheimer's disease: some general remarks

Etiopathogenesis of Alzheimer's disease: the “amyloid cascade hypothesis”

Molecular aspects of amyloid peptides and of their aggregation

Blocking Aβ amyloid aggregation as a strategy to contrast AD

Metal based compounds as tools for blocking amyloid aggregation

Advantages and disadvantages in the use of metal based compounds as experimental anti-AD agents

Conclusions and perspectives

Acknowledgment

Neurobiol. Aging

Alzheimer's Demen.

BMC Geriatr.

Neuron

Biochem. Biophys. Res. Commun.

Neurobiol. Aging

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Mol. Biol.

J. Mol. Biol.

J. Mol. Biol.

J. Mol. Biol.

Curr. Opin. Struct. Biol.

J. Mol. Biol.

J. Biol. Chem.

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Int. J. Biochem. Cell Biol.

Biophys. J.

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

Am. J. Public Health

Eur. J. Neurol.

Acta Neurol. Scand.

Acta Neurol. Scand.

Neurology

Int. J. Geriatr. Psychiatry

Int. J. Geriatr. Psychiatry

Annu. Rev. Public Health

Science

Nat. Rev. Drug Discov.

Nature

Proc. Natl. Acad. Sci. U.S.A.

EMBO J.

Nat. Chem.

Eur. J. Biochem.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Protein Sci.

FEBS J.

ChemBioChem

Biochemistry

J. Phys. Chem. B

FEBS J.

Review
Metal compounds as inhibitors of β-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer's disease