Abstract
SUMMARYAlzheimer’s disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4–10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.
Highlights
Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder that is characterised by the accumulation of extracellular -amyloid (A ) plaques, neurofibrillary tangles composed of hyperphosphorylated tau, neuronal loss and neuroinflammation (Frank-Cannon et al, 2009; Ballard et al, 2011)
The first apparent change was an advance in the daily temperature rhythms in 4-month-old 3xTgAD mice; by 6 months of age, mean body temperature and the amplitude of temperature rhythms were increased
No changes in activity were noted until 10 months of age, when mean activity and amplitude of activity rhythms were found to be higher in 3xTgAD mice than in controls
Summary
Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder that is characterised by the accumulation of extracellular -amyloid (A ) plaques, neurofibrillary tangles composed of hyperphosphorylated tau, neuronal loss and neuroinflammation (Frank-Cannon et al, 2009; Ballard et al, 2011). Patients with AD suffer from non-cognitive behavioural symptoms, such as depression, anxiety, agitation, weight loss, hyperactivity and disturbed circadian rhythms and sleep (Assal and Cummings, 2002; Gillette-Guyonnet et al, 2007; Bombois et al, 2010; Klaffke and Staedt, 2006; Stoppe et al, 1999; Finkel, 2003). These non-cognitive behavioural symptoms might not be a consequence of AD neuropathology, but instead could be a predictor of the disease. Understanding when and how these non-cognitive symptoms of AD occur could lead to a better quality of life for AD patients
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