Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: a role for cholinergic transmission.
The Tg2576 mouse model of Alzheimer's disease (AD) exhibits age-dependent amyloid beta (Abeta) deposition in the brain. We studied electroencephalographically defined sleep and the circadian regulation of waking activities in Tg2576 mice to determine whether these animals exhibit sleep abnormalities akin to those in AD. In Tg2576 mice at all ages studied, the circadian period of wheel running rhythms in constant darkness was significantly longer than that of wild type mice. In addition, the increase in electroencephalographic delta (1-4 Hz) power that occurs during non-rapid eye movement sleep after sleep deprivation was blunted in Tg2576 mice relative to controls at all ages studied. Electroencephalographic power during non-rapid eye movement sleep was shifted to higher frequencies in plaque-bearing mice relative to controls. The wake-promoting efficacy of the acetylcholinesterase inhibitor donepezil was lower in plaque-bearing Tg2576 mice than in controls. Sleep abnormalities in Tg2576 mice may be due in part to a cholinergic deficit in these mice. At 22 months of age, two additional deficits emerged in female Tg2576 mice: time of day-dependent modulation of sleep was blunted relative to controls and rapid eye movement sleep as a percentage of time was lower in Tg2576 than in wild type controls. The rapid eye movement sleep deficit in 22 month-old female Tg2576 mice was abolished by brief passive immunization with an N-terminal antibody to Abeta. The Tg2576 model provides a uniquely powerful tool for studies on the pathophysiology of and treatments for sleep deficits and associated cholinergic abnormalities in AD.
Wisor
J P
JP
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Edgar
D M
DM
Yesavage
J
J
Ryan
H S
HS
McCormick
C M
CM
Lapustea
N
N
Murphy
G M
GM
D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002799:Cholinergic Fibers / Q000502:physiology*; D021081:Chronobiology Disorders / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012890:Sleep / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics*