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

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.

Keywords: Alzheimer’s disease; MAPT; cognitive decline; diabetes; insulin resistance; tau protein; tauopathy.

Figure 1

Tau pathology as a mediator of insulin resistance and cognitive and metabolic alterations. Under pathological conditions, Tau loss of function can negatively impact the brain and peripheral tissues, such as skeletal muscle, adipose tissue and pancreas. In this review article, we explore the hypothesis of Tau pathology being a key inductor of insulin resistance and beta cell dysfunction in Alzheimer’s disease (AD) and other tauopathies. When defective insulin signaling is present in the brain, it triggers neurodegeneration and cognitive decline. On the other hand, when it is present in peripheral tissues, it leads to a diabetes-like phenotype. Inflammation, oxidative stress, hormonal dysregulation and neurotransmitter imbalance are mechanisms that can lead to/aggravate Tau pathology-induced alterations in insulin signaling/secretion in the brain and in the periphery, which are further associated with cognitive defects.