The Link Between Tau and Insulin Signaling: Implications for Alzheimer's Disease and Other Tauopathies.

Rafaella Araujo Gonçalves,Paul E Fraser,Fernanda G De Felice,Nadeeja Wijesekara

doi:10.3389/fncel.2019.00017

Abstract

The microtubule-associated protein tau (MAPT) is mainly identified as a tubulin binding protein essential for microtubule dynamics and assembly and for neurite outgrowth. However, several other possible functions for Tau remains to be investigated. Insulin signaling is important for synaptic plasticity and memory formation and therefore is essential for proper brain function. Tau has recently been characterized as an important regulator of insulin signaling, with evidence linking Tau to brain and peripheral insulin resistance and beta cell dysfunction. In line with this notion, the hypothesis of Tau pathology as a key trigger of impaired insulin sensitivity and secretion has emerged. Conversely, insulin resistance can also favor Tau dysfunction, resulting in a vicious cycle of these events. In this review article, we discuss recent evidence linking Tau pathology, insulin resistance and insulin deficiency. We further highlight the deleterious consequences of Tau pathology-induced insulin resistance to the brain and/or peripheral tissues, suggesting that these are key events mediating cognitive decline in Alzheimer’s disease (AD) and other tauopathies.

Highlights

Tau protein was first isolated from the porcine brain as a factor essential for microtubule assembly (Weingarten et al, 1975)
Protein phosphatase 2 (PP2A) is the primary Tau phosphatase implicated in Alzheimer’s disease (AD), the activity of which is suppressed by insulin administration in humans and animals (Gong et al, 1995; Kins et al, 2001; Vogelsberg-Ragaglia et al, 2001)
Despite the detection of markers of both Tau pathology and insulin resistance in exosomes derived from AD patients, it still remains to be elucidated how these species interact with each other regarding cause and consequence, their potential to act as trans-synaptic transmitter of pathology across neurons and their implication on brain function

Summary

INTRODUCTION

Tau protein was first isolated from the porcine brain as a factor essential for microtubule assembly (Weingarten et al, 1975). Tau is a natively soluble and unfolded protein that undergoes a variety of post-translational modifications (PTMs), which directly or indirectly modulates its physiological and pathological functions. Due to its scaffolding property, Tau can bind to a variety of proteins, impacting multiple physiological functions (Meier et al, 2015; Suzuki and Kimura, 2017; Zhou et al, 2017; Stefanoska et al, 2018). Many of these interactions still remain to be uncovered. A thorough understanding of the mechanisms linking Tau and insulin signaling becomes important when elucidating the increased risk of dementia associated with diabetes

Tau PROTEIN AND INSULIN SIGNALING IN THE BRAIN

Tau PROTEIN AND INSULIN SIGNALING IN PERIPHERAL TISSUES

CONCLUSION

AUTHOR CONTRIBUTIONS