Clioquinol Decreases Amyloid-β Burden and Reduces Working Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Grossi, Cristina^a | Francese, Simona^{b; d} | Casini, Angela^c | Rosi, Maria Cristina^a | Luccarini, Ilaria^a | Fiorentini, Anna^a | Gabbiani, Chiara^c | Messori, Luigi^c | Moneti, Gloriano^a | Casamenti, Fiorella^{a; *}

Affiliations: [a] Department of Pharmacology, University of Florence, Florence, Italy | [b] Mass Spectrometry Center, University of Florence, Florence, Italy | [c] Laboratory of Metals in Medicine (METMED), Department of Chemistry, University of Florence, Sesto Fiorentino, Florence, Italy | [d] Present address: Sheffield Hallam University, Biomedical Research Centre, Sheffield, UK

Correspondence: [*] Corresponding author: Dr. Fiorella Casamenti, Department of Pharmacology, Viale G. Pieraccini, 6, 50139 Florence, Italy. Tel.: +39 055 4271242; Fax: +39 055 4271280; E-mail: fiorella.casamenti@unifi.it.

Note: [] Communicated by Juha Rinne

Abstract: Clioquinol (CQ) is a "metal protein attenuating compound" that crosses the blood-brain barrier and binds, with high affinity, copper(II) and zinc(II), two metal ions critically involved in amyloid-β aggregation and toxicity. CQ was recently proposed for the treatment of Alzheimer's disease, but controversial data have been reported so far concerning its real therapeutic advantages. We describe here results of chronic CQ treatment in the TgCRND8 mouse model of Alzheimer's disease. Remarkably, based on classical behavioral tests, CQ treatment was found to revert, to a large extent, the working memory impairments that are characteristic of this mouse model. Pairwise, a significant reduction of amyloid-β plaque burden, both in the cortex and in the hippocampus, was detected as well as an attenuation of astrogliosis. MALDI Mass Spectrometry Imaging technique revealed a specific localization of CQ in the above mentioned brain areas. Modest but significant effects on the absolute and relative brain concentrations of the three most important biometals (i.e., copper, zinc, and iron) were highlighted following CQ treatment. The pharmacological and mechanistic implications of the above findings are thoroughly discussed.

Keywords: Alzheimer's disease, amyloid-β burden, behavioral tests, clioquinol, ICP-OES, MALDI-MSI, TgCRND8 mice

DOI: 10.3233/JAD-2009-1063

Journal: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 423-440, 2009