Tau deletion promotes brain insulin resistance

作者：Elodie Marciniak, Antoine Leboucher, Émilie Caron, Tariq Ahmed, Anne Tailleux, Julie Dumont, Tarik Issad, Ellen Gerhardt, Patrick Pagésy, Margaux Vileno, Clément Bournonville, Malika Hamdane, Kadiombo Bantubungi, Steve Lancel, Dominique Demeyer, Sabiha Eddarkaoui, Emmanuelle Vallez, Didier Vieau, Sandrine Humez, Émilie Faivre, Benjamin Grenier‐Boley, Tiago F. Outeiro, Bart Staels, Philippe Amouyel, Detlef Balschun, Luc Buée, David Blum · 发表于：The Journal of Experimental Medicine · 年份：2017 · DOI：10.1084/jem.20161731 · 被引用次数：203 · 研究领域：Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research、Biochemical effects in animals

The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.