Degeneration and energy shortage in the suprachiasmatic nucleus underlies the circadian rhythm disturbance in ApoE-/-mice: implications for Alzheimer's disease.
Alzheimer's disease (AD) patients suffer sleep disorders and circadian rhythm disturbances (CRDs). The underlying mechanisms are incompletely understood, and treatments are lacking. In this study, we characterized the locomotor activity, clock gene expression, morphological degeneration and energy metabolism of suprachiasmatic nucleus (SCN), together with retinal light sensing, in ApoE-/-mice, a model for AD. Compared with the control C57BL/6J mice, ApoE-/-mice exhibited disordered circadian locomotor activity under dim light and constant darkness, with impaired re-entrainment to phase change schedules. Decreased retinal melanopsin expression, together with amyloidosis and tau deposition, was evident in ApoE-/-mice. Mitochondrial and synaptic deterioration, altered SIRT1-mediated energy metabolism and clock gene expression were also observed in ApoE-/-SCN. Supplementation with fat or ketone bodies but not glucose, or intraperitoneal administration of nicotinamide, restored the locomotor rhythmicity and circadian expression of SIRT1 and clock genes, as well as reducing neurodegeneration. Taken together, ApoE deficiency induced degeneration and a significant disturbance in the SCN rhythmicity. Decline of retinal light sensing and SCN structural and metabolic deteriorations represented the major pathologies accounting for the CRDs in ApoE-/-mice. Our curative experiments may help develop future therapies to treat the CRDs and sleep disorders in AD patients.
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Lan
L
Zhou
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Qian
Q
Gao
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Meng
M
Nie
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Jing-Li
JL
Gu
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Wei
W
Hao
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Lin
L
Wang
Department of Physiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Institute of Basic Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China.
Ji-Min
JM
Cao
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism*; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004734:Energy Metabolism; D008027:Light; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D008928:Mitochondria / Q000473:pathology; D010775:Photic Stimulation; D056564:Sirtuin 1 / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000473:pathology* / Q000503:physiopathology
D056926:CLOCK Proteins; C538944:Clock protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1