Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease

Neurobiol Aging. 2016 Jul;43:47-57. doi: 10.1016/j.neurobiolaging.2016.03.024. Epub 2016 Mar 30.


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 triple-transgenic mouse model of AD (3×Tg-AD) spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared with age-matched controls. This was despite higher nonshivering thermogenic activity, as evidenced by brown adipose tissue norepinephrine content and uncoupling protein 1 expression. A 24-hour exposure to cold (4 °C) aggravated key neuropathologic markers of AD such as: tau phosphorylation, soluble amyloid beta concentrations, and synaptic protein loss in the cortex of 3×Tg-AD mice. Strikingly, raising the body temperature of aged 3×Tg-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.

Keywords: 3×Tg-AD; Alzheimer's disease; Cold exposure; Thermogenesis; Thermoneutrality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Alzheimer Disease / therapy
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Body Temperature / physiology
  • Body Temperature Regulation*
  • Cold Temperature / adverse effects
  • Disease Models, Animal
  • Energy Metabolism / physiology
  • Mice, Transgenic
  • Norepinephrine / metabolism
  • Phosphorylation
  • Synapses / pathology
  • Temperature*
  • Thermogenesis / physiology*
  • Uncoupling Protein 1 / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Uncoupling Protein 1
  • tau Proteins
  • Norepinephrine