Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease

• DOI: 10.1007/s00018-012-1047-9
• Publication Date: 2012-06-21T14:40:58Z
• Authors: Yasmina Manso; Javier Carrasco; Gemma Comes; Gabriele Meloni; Paul A. Adlard; Ashley I. Bush; Milan Vašák; Juan Hidalgo
• Keywords: Male; 0301 basic medicine; 590; 2804 Cellular and Molecular Neuroscience; 610; Mice, Transgenic; Nerve Tissue Proteins; Hippocampus; 1307 Cell Biology; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Alzheimer Disease; 616; 10019 Department of Biochemistry; 1312 Molecular Biology; Animals; Humans; Mice, Knockout; Amyloid beta-Peptides; Behavior, Animal; Body Weight; Metallothionein 3; Peptide Fragments; 3. Good health; Disease Models, Animal; 3004 Pharmacology; 1313 Molecular Medicine; 570 Life sciences; biology; Female

Among the dementias, Alzheimer's disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn(7)MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.