Mind how you go: The current strategies for the development of therapies for Alzheimer's disease are very diverse. Particular attention is given to the search for inhibitors (see picture for two examples) of the proteolytic enzyme beta- and gamma-secretase, which inhibits the cleavage of the amyloid precursor proteins into amyloid beta peptides, from which the disease-defining deposits of plaque in the brains of Alzheimer's patients originates.Research on senile dementia and Alzheimer's disease covers an extremely broad range of scientific activities. At the recent international meeting of the Alzheimer's Association (ICAD 2008, Chicago) more than 2200 individual scientific contributions were presented. The aim of this Review is to give an overview of the field and to outline its main areas, starting from behavioral abnormalities and visible pathological findings and then focusing on the molecular details of the pathology. The "amyloid hypothesis" of Alzheimer's disease is given particular attention, since the majority of the ongoing therapeutic approaches are based on its theoretical framework.

Alzheimer's Disease: From Pathology to Therapeutic Approaches

In the present perspective, we give a critical review on the coordination chemistry of the metal ions copper and zinc to the amyloid-β (Aβ) peptide; such complexes have been linked to Alzheimer's disease. We focus on two main issues: the identification of the coordination sphere of the Cu(II) and Zn(II) ions and the affinity of these metal ions towards the peptide. With the aim to come up with as few as possible valuable structural models and binding affinity values, we critically review the divergent propositions reported in the literature and take into account the experimental differences and the limits of the methods used in the published studies. We propose that: (i) the conditional dissociation constant of the Cu(Aβ) complexes lies in the range of 10 pM to 100 nM, with a preference for the region between 100 pM to 1 nM. (ii) Two most likely coordination modes for the predominant form of the Cu(Aβ) complexes at physiological pH can be retained, both being 3N1O distorted square planar. In the first model, the Cu(II) ion is coordinated by the Nτ atoms of the three His residues and the carboxylate of the Asp1. In the second model, both the N-terminus and the carboxylate functions of Asp1 are ligated together with the Nτ of His6 and of His13 (or His14). An equilibrium between these two forms at room temperature, and a preferentially freezing out of the second one would explain most of the divergences in the published results (in particular, between those obtained by EPR and NMR). (iii) The apparent dissociation constants of Zn(Aβ) in various buffers are in the range of 1 to 20 μM (a 10 times lower conditional dissociation constant can be estimated. (iv) For the Zn(II) coordination, the implication of the three His and the Asp1 residues is consensual. The Asp1 can be coordinated by the carboxylate and/or the N-terminus functions. Additional ligands are possible, such as Glu11 or H2O.

Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-β peptide

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease The brain is particularly vulnerable to oxidative damage induced by unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence of metal dyshomeostasis and increased oxidative stress The colocalisation of copper and amyloid β (Aβ) in the glutamatergic synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of redox-potent Aβ with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the formation of neurotoxic soluble Aβ oligomers Interactions between Aβ oligomers and copper can further promote the aggregation of Aβ, which is the core component of extracellular amyloid plaques, a central pathological hallmark of AD Copper dysregulation is also implicated in the hyperphosphorylation and aggregation of tau, the main component of neurofibrillary tangles, which is also a defining pathological hallmark of AD Therefore, tight regulation of neuronal copper homeostasis is essential to the integrity of normal brain functions Therapeutic strategies targeting interactions between Aβ, tau and metals to restore copper and metal homeostasis are discussed

Copper in the brain and Alzheimer's disease.

Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases.

With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one-compound-one-target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium-permeable channels such as voltage-dependent calcium channels, N-methyl-D-aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one-compound-various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD.

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

The binding stoichiometry between Cu(II) and the full-length β-amyloid Aβ(1−42) and the oxidation state of copper in the resultant complex were determined by electrospray ionization−Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry The same approach was extended to the copper complexes of Aβ(1−16) and Aβ(1−28) A stoichiometric ratio of 1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the complexes, and residues tyrosine-10 and methionine-35 are not oxidized in the Aβ(1−42)−Cu(II) complex The stoichiometric ratio remains the same in the presence of more than a 10-fold excess of Cu(II) Redox potentials of the sole tyrosine residue and the Cu(II) center were determined to be ca 075 and 008 V vs Ag/AgCl [or 095 and 028 V vs normal hydrogen electrode (NHE)], respectively More importantly, for the first time, the Aβ−Cu(I) complex has been generated electrochemically and was found to catalyze the reduction of ox

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Lijie Men

Papers

Redox Reactions of Copper Complexes Formed with Different β-Amyloid Peptides and Their Neuropathalogical Relevance†