Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Final Activity and Management Report Summary - MOLECULAR IMAGING (Molecular Imaging of Atherosclerosis)

Myeloperoxidase (MPO) is a key component of the antimicrobial armoury of neutrophils. In the presence of hydrogen peroxide, MPO can generate a variety of reactive oxygen species against microorganisms. Besides its role in host defence, MPO has been implicated in the pathophysiology of cardiovascular and neurodegenerative diseases, likely by causing an increase in oxidative stress. During the first part of the project, three new compounds were synthesised and well-characterised as substrates for MPO detection.

These compounds were based on the conjugation of aromatic amines which can interact with the MPO, to the chelating agent, DTPA, which allows these compounds to complex with the gadolinium ion, making these compounds into imaging agents for Magnetic Resonance Imaging (MRI). The ability of our compounds to interact with myeloperoxidase depends on the redox potential values of the resultant imaging agents and the interaction of the complexes with the MPO results in radical generation. Indeed, it has been reported that an increase of MPO expression and related oxidative products were found in neurons in human patients with Alzheimer's disease (AD). Therefore, we aimed to identify if the myeloperoxidase enzyme would be a good biomarker to detect AD.

We identified intracellular MPO in 3xTg-AD mice at the early phases of the disease (6-7 months) by immunohistochemistry techniques. The labelling was stronger in older animals. MPO was mainly detected in the pyramidal neurons of hippocampus and amygdala, which are also the preferential sites of intraneuronal amyloid-? deposits in this AD animal model. Confirming last result, RT-PCR showed an increase in the MPO expression in transgenic mice versus control mice. In vitro MPO characterisation using the neuronal cell line, MC65, which mimics the accumulation of the amyloid-? in neurons by expression of a partial APP fusion protein, was carried out. An increase in the MPO activity and in the expression was observed due to the accumulation of amyloidogenic peptides, confirming the active paper of the MPO in AD.

Finally, since AD presents from the beginning of the disease a chronic inflammatory response, we created an inflammatory scenario using a mix of cytokines: Il-1? and IFN-? and we treated the human neuronal cell line SK-NMC with them. After treatment, MPO activity had increased, confirming the inflammatory role of the MPO in neurons at the very early stage of the disease. All these results suggest that our MRI imaging probes that target MPO could be used to detect AD prior to the development of amyloid-? deposits.

Reported by

SPANISH COUNCIL FOR SCIENTIFIC RESEARCH
MADRID
Spain