Impaired thermoregulation and beneficial effects of thermoneutrality in the 3xTg-AD model of Alzheimer’s disease (AD)

Abstract The sharp rise in the incidence of Alzheimer’s disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the 3xTg-AD mouse model of AD spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared to age-matched controls. This was despite higher non-shivering thermogenic activity, as evidenced by brown adipose tissue (BAT) norepinephrine content and uncoupling protein 1 (UCP1) expression. A 24-h exposure to cold (4°C) aggravated key neuropathological markers of AD such as: tau phosphorylation, soluble Aβ concentrations and synaptic protein loss in the cortex of 3xTg-AD mice. Strikingly, raising the body temperature of aged 3xTg-AD mice via exposure to a thermoneutral environment improved memory function and reduced amyloid and synaptic pathologies within a week. Our results suggest the presence of a vicious cycle between impaired thermoregulation and AD-like neuropathology and it is proposed that correcting thermoregulatory deficits might be therapeutic in AD.