Neophobia, NQO1 and SIRT1 as premorbid and prodromal indicators of AD in 3xTg-AD mice.
Increased oxidative stress seems to be a key factor underlying natural processes of aging, but also to occur prior to neuropathological hallmarks of neurodegenerative diseases. The present work studied the temporal variation of three key antioxidant enzymes in cortex and hippocampus during the development of behavioral and cognitive symptoms in 3xTg-AD mice, and as compared to age-matched controls. At 2 months of age, when no intraneuronal Aβ immunoreactivity has been reported, increased neophobia shown as a delayed and reduced rearing, evidenced the onset of BPSD-like symptoms at premorbid stages of disease. In these animals, NQO1 was found increased in both the hippocampus (800%) and cortex (400%) and progressively diminished at older ages. SOD1 was increased in the hippocampus at 4 months of age, when neuronal Aβ accumulation has been established. These hippocampal increases of antioxidants before the prodromal emergence of cognitive symptoms support their role as defense mechanisms. SIRT1 levels showed opposite age-dependent changes in cortex (increase) and hippocampus (decrease) relative to controls. Prodromal cognitive deficits emerged at 6 months of age, concomitantly to cortical overexpression of SIRT1 but down-regulation of NQO1 and SIRT1 in the hippocampus, suggesting inadequate antioxidative protection to prevent or delay the subjacent neuronal damage. The present data further support the link between oxidative status and the anxious profile. Their crosstalk may underline AD-pathological mechanisms that may lead to deranged physiology and selective neuronal degeneration. It also points out increased neophobia and high expression of NQO1 among the first indicators of disease in the 3xTg-AD mice.
Department of Psychiatry and Forensic Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Institut of Neurocience, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Virginia
V
Torres-Lista
Department of Medical Sciences, Faculty of Medicine of Ciudad Real, University of Castilla La Mancha, Ciudad Real, Spain; Centro Regional de Investigaciones Biomédicas, Universidad de Castilla la Mancha, Spain.
Cristina
C
Parrado-Fernández
Department of Psychiatry and Forensic Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Institut of Neurocience, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Ismael
I
Alvarez-Montón
Department of Medical Sciences, Faculty of Medicine of Ciudad Real, University of Castilla La Mancha, Ciudad Real, Spain.
Javier
J
Frontiñán-Rubio
Department of Medical Sciences, Faculty of Medicine of Ciudad Real, University of Castilla La Mancha, Ciudad Real, Spain; Centro Regional de Investigaciones Biomédicas, Universidad de Castilla la Mancha, Spain.
Mario
M
Durán-Prado
Department of Medical Sciences, Faculty of Medicine of Ciudad Real, University of Castilla La Mancha, Ciudad Real, Spain; Centro Regional de Investigaciones Biomédicas, Universidad de Castilla la Mancha, Spain.
Juan Ramón
JR
Peinado
Department of Neuroscience, Karolinska Institutet, KS CMM L8:01, SE-171 76 Stockholm, Sweden.
Björn
B
Johansson
Department of Medical Sciences, Faculty of Medicine of Ciudad Real, University of Castilla La Mancha, Ciudad Real, Spain; Centro Regional de Investigaciones Biomédicas, Universidad de Castilla la Mancha, Spain. Electronic address: franciscoj.alcain@uclm.es.
Francisco Javier
FJ
Alcaín
Department of Psychiatry and Forensic Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Institut of Neurocience, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain. Electronic address: lidia.gimenez@uab.cat.
Lydia
L
Giménez-Llort
D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D016564:Amyloid beta-Protein Precursor; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
3xTg-AD mouse; AD-C; AD-P; Alzheimer's disease; Antioxidant enzymes; Behavior