Tau deletion promotes brain insulin resistance

被引:167
作者
Marciniak, Elodie [1 ,2 ]
Leboucher, Antoine [1 ,2 ]
Caron, Emilie [1 ]
Ahmed, Tariq [3 ,8 ]
Tailleux, Anne [4 ]
Dumont, Julie [2 ,5 ]
Issad, Tarik [6 ]
Gerhardt, Ellen [7 ]
Pagesy, Patrick [6 ]
Vileno, Margaux [1 ,2 ]
Bournonville, Clement [1 ,2 ]
Hamdane, Malika [1 ,2 ]
Bantubungi, Kadiombo [4 ]
Lancel, Steve [4 ]
Demeyer, Dominique [1 ,2 ]
Eddarkaoui, Sabiha [1 ,2 ]
Vallez, Emmanuelle [4 ]
Vieau, Didier [1 ,2 ]
Humez, Sandrine [1 ,2 ]
Faivre, Emilie [1 ,2 ]
Grenier-Boley, Benjamin [2 ,5 ]
Outeiro, Tiago F. [7 ]
Staels, Bart [4 ]
Amouyel, Philippe [2 ,5 ]
Balschun, Detlef [3 ]
Buee, Luc [1 ]
Blum, David [1 ,2 ]
机构
[1] Univ Lille, INSERM, CHU Lille, UMR S 1172,JPArc, Lille, France
[2] LabEx DISTALZ Dev Innovat Strategies Transdiscipl, Lille, France
[3] Katholieke Univ Leuven, Fac Psychol & Educ Sci, Lab Biol Psychol, Leuven, Belgium
[4] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,U1011EGID, Lille, France
[5] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,RID AGE Facteurs Risque & Dete, Lille, France
[6] Univ Paris 05, Sorbonne Paris Cite, Inst Cochin, INSERM U1016,CNRS UMR8104, Paris, France
[7] Univ Med Ctr Goettingen, Ctr Nanoscale Microscopy & Mol Physiol Brain, Dept Expt Neurodegenerat, Gottingen, Germany
[8] Hamad Bin Khalifa Univ, Qatar Biomed Res Inst, Neurol Disorders Res Ctr, Doha, Qatar
关键词
ALZHEIMERS-DISEASE; RECEPTOR SUBSTRATE; AMYLOID-BETA; BODY-WEIGHT; NEUROFIBRILLARY TANGLES; CEREBROSPINAL-FLUID; FOOD-INTAKE; PHOSPHORYLATION; PROTEIN; GLUCOSE;
D O I
10.1084/jem.20161731
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:2257 / 2269
页数:13
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