Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model.

Hamza Benderradji,Bryan Thiroux,Anne Muhr-Tailleux,Sabiha Eddarkaoui,Mélanie Besegher,Nicolas Sergeant,Didier Vieau,Kadiombo Bantubungi,Laure Rolland,Cyril Bourouh,Theo Boschetti,Antonino Bongiovanni,Steve Lancel,Anna Bogdanova,Emilie Nicolas,Kévin Carvalho,Sarra Kraiem,Luc Buée,Thibaut Gauvrit,David Blum,Émilie Courty ,Émilie Faivre ,Frédérik Oger ,Jean-Sébastien Annicotte ,Emmanuelle Caron ,Victoria Gómez-Murcia ,Valérie Buée‐Scherrer

doi:10.3389/fnmol.2022.841892

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.

Highlights

Neurofibrillary degeneration, made of aggregates of hyper- and abnormally phosphorylated tau proteins is a neuropathological hallmark of tauopathies including Alzheimer’s disease (AD; Sergeant et al, 2008; Colin et al, 2020)
We have performed a metabolic evaluation, focusing on glucose homeostasis, of tau KI mice in which the human 1N4R isoform mutated at P301L has been inserted at the locus of the mouse Mapt gene
To fully appreciate the functional impact of tau loss-of-function on tau KI mice to β-cell function, we evaluated glucosestimulated insulin secretion (GSIS) in low and high glucose conditions from pancreatic islets isolated from WT, tau KI mice, and tau KO male mice, taken as a control

Summary

Introduction

Neurofibrillary degeneration, made of aggregates of hyper- and abnormally phosphorylated tau proteins (tau pathology) is a neuropathological hallmark of tauopathies including Alzheimer’s disease (AD; Sergeant et al, 2008; Colin et al, 2020) In the latter, the spatiotemporal progression of tau pathology has been tightly correlated to cognitive deficits, Tau and Glucose Homeostasis supporting an instrumental role (Colin et al, 2020). Tau knock-out or knock-down models display similar alterations (Ahmed et al, 2015; Biundo et al, 2018; Velazquez et al, 2018) These latter observations support that tau, essentially expressed by neurons in the nervous system, exerts physiological functions whose loss promotes neuron-autonomous dysfunctions. The physiological functions of tau remain ill-defined

Methods

Results

Conclusion