Il ruolo di ioni di rame nella neurodegenerazione: modelli molecolari

Responsabili di progetto

Giovanni Lapenna, Suan Li Mai

Accordo

POLONIA - PAS (NUOVO ACCORDO) - Polish Academy of Sciences/Polska Akademia Nauk

Bando

CNR-PAN 2017-2019

Dipartimento

Scienze chimiche e tecnologie dei materiali

Area tematica

Scienze chimiche e tecnologie dei materiali

Stato del progetto

Nuovo

Proposta di ricerca

Neurodegeneration is the process of neuronal death. Apart from traumatic and infectious events (virus and bacteria the most frequent cause of necrosis), cells dye for apoptosis, that is a programmed death (DNA demolition) induced by the loss of cellular correct homeostasis during the interphase. When this event is phisiological it is followed by a recicling of the demolished cell components. In the organized central nervous system this recicling is not functional, being the neuronal architecture less plastic by construction, and cognitive impairment occurs. The signals for apoptosis are multiple, but the change in oxidoreductive properties or the change in membrane stability are some of the most general. These events are related to others, like the occurrence of radical chemical species or ions dishomeostasis [Gutteridge94].
Molecular fingerprints of neurodegeneration are in most of the cases unusual deposits of proteins both within the cytoplasm and in the extracellular matrix [Selkoe03]. As for Alzheimer's disease (dementia), the deposit of amyloid peptides in the extracellular matrix are formed by peptides of 39-42 aminoacids (termed amyoloid beta peptides, Abeta) produced by a pathological fragmentation of the amyloid precursor membrane protein (APP). Several d-block cations like Zn, Fe and Cu are found in the deposits in relatively high concentration [Lovell98]. The association between these deposits and the neuronal death has been described in the amyloid cascade hypothesis [Hardy02]. Despite the hypothesis be criticized and updated, todate there is consensus that amyloid aggregation triggers the neuronal death, meaning that the cause is upstream to amyloid peptide cumulation, but the presence of large amounts of amyloid peptides, together with other cofactors, speeds up the processes, signaling the loss of neuronal function and the consequent apoptosis. More importantly, the trigger can be operated by soluble and mobile oligomers that can propagate the amyloid cascade within the tissue [Haas07].
Among the cofactors, d-block cations are important, because the chemical species formed by amyloid peptides and ions like Fe and Cu are potentially aggressive as catalysts for oxidoreductive reactions otherwise silenced by folded enzymes and metal ion transporters. Moreover, the release by other proteins of Cu and Fe (ions dishomeostasis) due to a general unfolding process, allows to connect the amyloid hypothesis with those processes related to aging.
In this project the two involved laboratories, within the respective already established collaborations with other european laboratories involved in the same research, will develop a modeling strategy aiming at providing to biologists chemical models of the aggressive catalysts emerging during the amyloid cascade. The project deals with Cu-amyloid beta peptide oligomeric complexes, the latter recognized as efficient and soluble catalysts for dioxygen activation both in vitro and in cell cultures. The models will be essential pieces of information in the basic research concerning the molecular mechanisms of neurodegeneration beyond the specific case of dementia. The knowledge of the molecular mechanism of neurodegeneration provides a guideline for an early detection of the signs of the disease, thus possibly preventing relatively young persons to rapidly fall in an irreversible and long-term disease.
The project stems from a previoius bilateral project between Cnr (I) and CNRS (F), involving the collaboration between the laboratory in Firenze (Cnr-ICCOM) and C. Hureau and P. Faller in Toulose (LCC-CNRS). The collaboration produced several important research articles where both in vitro experiments and related molecular models demonstrated the activation of dioxygen to superoxide exerted by Cu-Abeta dimeric complexes [LaPenna2013,Reybier2016,Mirats2015]. The following collaboration between the laboratory in Firenze and the computational group of Mai Suan Li in Warsaw (PL) described in detail the effect of Cu-Abeta binding on the solubility of the peptide, thus showing that the 1:1 Cu:Abeta ratio provides an efficient mechanism to the diffusion of toxic species between neurons [Huy2016].
The idea behind this proposal for a bilateral project between the group in Firenze (Cnr-ICCOM, I) and that in Warsaw (PAN, Institute of physics, PL) is that the combination of modeling techniques and human resources of the two modeling units will increase the size and statistics of the models, thus attracting more interest by biologists and physicians. The european-scale modeling unit will constitute a seed for the development of an european project devoted to early diagnosis of neurodegeneration by addressing low traces of biologically released Cu ions as the target biomarker.

[Gutteridge94] JM Gutteridge, B Halliwell,l Antioxidants in Nutrition, Health and Disease, Oxford Univ. press, 1994.
[Selkoe03] DJ Selkoe, Folding proteins in fatal ways, Nature, 2003.
[Lovell98] MA Lovell et al., Copper, Iron and Zinc in Alzheimer's Disease Senile Plaques, J. Neurol. Sci., 1998.
[Hardy02] J Hardy et al, The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems On the Road to Therapeutics, Science, 2002.
[Haas07] C Haas et al, Soluble Protein Oligomers in Neurodegeneration: Lessons From the Alzheimer's Amyloid beta-Peptide, Nat. Rev. Mol. Cell. Biol., 2007.
[Reybier2016] K Reybier et al, Free superoxide is an intermediate in the production of H2O2 by Copper(I)-A\beta peptide and O2, Angew. Chem., 2016.
[Mirats2015] A Mirats et al, Dioxygen activation in the Cu-amyloid beta complex, Phys. Chem. Chem. Phys., 2015.
[Huy2016] PDQ Huy et al, Impact of Cu(II) binding on Structures and Dynamics of Abeta42 Monomer and Dimer: Molecular Dynamics Study, ACS Chem. Neurosci., 2016.
[LaPenna2013] G La Penna et al, Identifying, By First-Principles Simulations, Cu[Amyloid-beta] Species Making Fenton-Type Reactions in Alzheimer's Disease, J. Phys. Chem. B, 2013

Obiettivi della ricerca

The goal of this project is to provide molecular models to chemists, biologists and physicians, in order to help the understanding of those events that trigger the neurodegenration. These models help in designing strategies to delay the process of neurodegeneration, thus providing a slower and less dramatic pathway to neurodegenerative diseases.
The project is focused on the role of copper ions in the Alzheimer's disease, stemming from the recent results showing that Cu-Abeta peptide, in certain configurations, activates dioxygen to produce aggressive hydroxil radicals.
The two involved laboratories are already working to model Abeta(1-42) peptides in dimeric and tetrameric forms, including Cu ions in different ratio. This modeling activity is supported by a DECI 13 (13th call of Deisa extreme computing initiative) project within the PRACE (Partnership for advanced computing in Europe) infrastructure. The bilateral project will provide an environment to exchange researchers within the two laboratories to achieve a more efficient usage of computational resources provided by the above EU infrastructure.
Starting from the results of the DECI 13 project, the catalytic properties of trimeric and tetrameric assemblies of Cu-Abeta, especially at a 1:1 Cu:Abeta ratio, will be investigated by using models based on density-functional theory approximations of electrons. In the meanwhile, coarse-grained approximations will be designed to approach larger Cu-Abeta assemblies, up to 10.

Ultimo aggiornamento: 19/04/2024