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Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model

Abstract : Alzheimer’s disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the β cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic β-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic β cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD.
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Submitted on : Monday, June 20, 2022 - 11:03:13 AM
Last modification on : Tuesday, June 28, 2022 - 9:15:14 AM

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Hamza Benderradji, Sarra Kraiem, Emilie Courty, Sabiha Eddarkaoui, Cyril Bourouh, et al.. Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model. Frontiers in Molecular Neuroscience, Frontiers Media, 2022, 15, pp.841892. ⟨10.3389/fnmol.2022.841892⟩. ⟨inserm-03699324⟩

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