Characterization of the role of metallothionein-3 in an animal model of Alzheimer's disease.
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.
Unidad de Fisiología Animal, Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Biociencias, Universidad Autónoma de Barcelona, Edificio C, Bellaterra, 08193 Barcelona, Spain.
Yasmina
Y
Manso
Javier
J
Carrasco
Gemma
G
Comes
Gabriele
G
Meloni
Paul A
PA
Adlard
Ashley I
AI
Bush
Milan
M
Vašák
Juan
J
Hidalgo
D000544:Alzheimer Disease / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D000090023:Metallothionein 3; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)