The prevalence of Alzheimer’s disease (AD), the most common cause of dementia nowadays, is expected to increase within the coming years, representing a serious threat for society and the healthcare system. For this reason, a lot of research is being devoted to unraveling the root physiological processes that ultimately lead to the onset of AD.

A𝛃 is a self-assembling peptide (peptide is a generic term for an amino acid chain, while large peptides are usually called proteins) that forms deposits, also called amyloid plaques, in the synaptic cleft. Such plaques have been observed in AD brains and are thought to interfere with neurological activity; however, they have also been detected in healthy brains. Intermediate A𝛃 aggregates called oligomers, comprised of a few A𝛃 molecules, are seemingly more toxic and better correlate with the disease.

Metal ions play crucial roles in the human body; nevertheless, they can cause serious damage to biomolecules and cells (such as DNA and neurons) when not submitted to tight regulation. Misbalanced levels of copper, which is involved in neurotransmission, have been found in AD brains where it generates oxidative stress, eventually leading to neuron dysfunction and death. Moreover, copper coenriches with A𝛃 peptide in the synaptic cleft, where it is believed to stabilize oligomers and enhance their toxicity.

Fig. 1.

Copper can induce changes to A𝛃 itself; for instance, two A𝛃 molecules can undergo irreversible binding through the amino acid tyrosine, resulting in A𝛃 dimers with increased stability. These dimers have been detected in AD patients, whereas they are rarely found in healthy individuals.

Hence, copper-capturing drugs represent a promising tool against AD as they may restore natural A𝛃 aggregation into (less toxic) amyloid plaques and prevent copper-mediated generation of oxidative stress. In this context, we have used short (3 amino acids) peptides of sequence HXH, where H is histidine (an effective copper binder) and X is a varying amino acid, which effectively displaced A𝛃-bound copper ions and prevented the production of oxidizing species.

Also, we have studied the role of A𝛃 dimers in the aggregation of the peptide, which remains unclear. For this reason, we have prepared dityrosine, a fluorescent model of the dimers made of two tyrosine residues. This model allowed us to detect and quantify the amount of A𝛃 dimers generated under different representative conditions and to evaluate their impact on amyloid formation. Upon incubation of A𝛃 with physiological concentrations of copper and hydrogen peroxide (H₂O₂, an oxidizing species abundant in AD dysfunctional mitochondria), up to 3% of A𝛃 dimers were detected, while only residual amounts were found for pure A𝛃 or in the presence of copper or H₂O₂ alone.

Next, we assessed the impact of such dimers on the amyloid generation process using thioflavin T, an amyloid-selective fluorescent dye. Surprisingly, a dimer proportion no greater than 3% was sufficient to completely inhibit amyloid formation (in the presence of both copper and H₂O₂). In contrast, when we incubated the A𝛃-copper-H₂O₂ system with the copper-binding tripeptide HAH (A = alanine), the production of dimers decreased to levels comparable to the A𝛃-H₂O₂ sample (without copper) and, most importantly, amyloid formation was restored.

In conclusion, we have shed light on the copper-mediated mechanism of A𝛃 oligomer stabilization by showing that, in the presence of copper and H₂O₂, low amounts of A𝛃 dimers hampered aggregation into amyloids. Furthermore, we restored natural amyloid formation by using a copper-binding agent, encouraging further exploration of copper depletion as a viable anti-AD approach. Our humble contribution adds to the massive combined effort of the scientific community which will undoubtedly lead to the victory of mankind over this devastating disease.

Guillem Vázquez, Ana B. Caballero
Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain

Publication

Copper, dityrosine cross-links and amyloid-β aggregation
Vázquez G, Caballero AB, Kokinda J, Hijano A, Sabaté R, Gamez P
J Biol Inorg Chem. 2019 Dec

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