TY - JOUR
T1 - Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease
AU - Bellanti, Francesco
AU - Iannelli, Giuseppina
AU - Blonda, Maria
AU - Tamborra, Rosanna
AU - Villani, Rosanna
AU - Romano, Adele
AU - Calcagnini, Silvio
AU - Mazzoccoli, Gianluigi
AU - Vinciguerra, Manlio
AU - Gaetani, Silvana
AU - Giudetti, Anna Maria
AU - Vendemiale, Gianluigi
AU - Cassano, Tommaso
AU - Serviddio, Gaetano
PY - 2017/1/1
Y1 - 2017/1/1
N2 - A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas-suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem-of 6-and 18-month-old Non-Tg and 3×Tg-AD mice after 12h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ϵ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.
AB - A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas-suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem-of 6-and 18-month-old Non-Tg and 3×Tg-AD mice after 12h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ϵ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.
KW - Aging
KW - Alzheimer's disease
KW - clock genes
KW - light exposure
KW - suprachiasmatic nucleus
UR - http://www.scopus.com/inward/record.url?scp=85024902006&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85024902006&partnerID=8YFLogxK
U2 - 10.3233/JAD-160942
DO - 10.3233/JAD-160942
M3 - Article
AN - SCOPUS:85024902006
VL - 59
SP - 615
EP - 631
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 2
ER -