Age-related changes in core body temperature and activity in triple-transgenic Alzheimer’s disease (3xTgAD) mice

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.

Tail-flick test response in 3×Tg-AD mice at early and advanced stages of disease

“…The results show that at both, early (6-7 months of age) and beginning of advanced stages of disease (11-12 months of age), the tail-flick response of male 3 × Tg-AD mice was similar to that of age-matched NTg mice, and far from what could be expected from their increased body core temperature [23]. In both genotypes, the latency to respond to the cold thermal stimulus was increased with age, in agreement with the age differences in the neurophysiology of nociception and the perceptual experience of pain [24].…”

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…These mice also displayed changes in the neuropeptidergic content of the SCN (AVP-and VIP-expressing neurons), a situation that echoes findings from postmortem studies of the SCN in AD. Another recent study on the 3xTg model shows exaggerated amplitude and a phase advance of the core body temperature rhythm, and these effects were not dependent on cyclooxygenase and occurred in the absence of neuropathology in the hypothalamus (67). Analysis of the AbPPswe/PSEN1A246E mouse-which carries transgenes for both APP and presenilin-1-shows that, although activity levels are increased, circadian organization of behavior is not increased (68).…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Additionally, genetic deletion of Tau resulted in increased body weight [152]. Impaired satiation and increased feeding behavior [153], as well as changes in body temperature [154] were also observed in a mouse model combining amyloid plaques and Tau pathology (3xTgAD). In Tg4510 mice, weight loss was specific to fat mass and co-occurred with deregulation of metabolic rate [151] as well as disturbances in circadian rhythm [98].…”