Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease

Neurobiology of Disease

Carl Julien¹  Noura B. El Khoury¹  Françoise Morin¹  Frédéric Calon¹  Robert A. Whittington²  Emmanuel Planel²  Andréanne Turgeon³  André Marette³  François Marcouiller³  Maud Gratuze³ 

[1] Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada;Centre de recherche du Centre Hospitalier de l'Université Laval de Québec, Axe Neurosciences, Québec, QC, Canada;Université Laval, Faculté de Médecine, Département de Psychiatrie et Neurosciences, Québec, QC, Canada;

关键词: Alzheimer's disease;    Diabetes mellitus;    ob/ob mice;    Tau hyperphosphorylation, hippocampus;    Kinase;    Phosphatase;   

DOI  :  

来源: DOAJ

【 摘 要 】

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM.Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia.Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

【 授权许可】

Unknown