TY - JOUR
T1 - Circadian system functionality, hippocampal oxidative stress, and spatial memory in the APPswePS1dE9 transgenic model of Alzheimer disease
T2 - Effects of melatonin or ramelteon
AU - Otalora, Beatriz Baño
AU - Popovic, Natalija
AU - Gambini, Juan
AU - Popovic, Miroljub
AU - Viña, José
AU - Bonet-Costa, Vicent
AU - Reiter, Russel J.
AU - Camello, Pedro Javier
AU - Rol, Maria Ángeles
AU - Madrid, Juan Antonio
N1 - Funding Information:
This project was funded by the Instituto de Salud Carlos III (RETICEF, RD06/0013/0019, RD06/0013/ 1012, RD06/0013/0027), the Ministry of Education and Science (BFU2010-21945-C02-01), Seneca Foundation (12005/PI/09), and a Research fellowship granted to B. B. Otalora (AP2006-04117).
PY - 2012/8
Y1 - 2012/8
N2 - Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswePS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (τ) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24h. Whereas melatonin maintained τ at 24h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswePS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD.
AB - Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswePS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (τ) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24h. Whereas melatonin maintained τ at 24h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswePS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD.
KW - Alzheimer disease
KW - Body temperature rhythm
KW - Circadian system
KW - Hippocampus
KW - Melatonin
KW - Oxidative stress
KW - Ramelteon
KW - Spatial memory
UR - http://www.scopus.com/inward/record.url?scp=84864231259&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864231259&partnerID=8YFLogxK
U2 - 10.3109/07420528.2012.699119
DO - 10.3109/07420528.2012.699119
M3 - Article
C2 - 22823866
AN - SCOPUS:84864231259
VL - 29
SP - 822
EP - 834
JO - Chronobiology International
JF - Chronobiology International
SN - 0742-0528
IS - 7
ER -