Tau deletion or loss of function promotes peripheral insulin resistance

Abstract

The epidemiological connection between Alzheimer's disease (AD) and type 2 diabetes display a critical health challenge worldwide. Insulin resistance has been identified as an important core feature in both diseases. However, the molecular mechanism underlying the crosstalk is still unclear and it is unknown if insulin resistance is a cause or a consequence of AD. Several studies have shown that insulin signaling is impaired in the brains of AD patients and AD transgenic mouse models, with little emphasis on how peripheral insulin signaling operate in AD, or whether peripheral insulin resistance precedes or succeeds central insulin resistance. Moreover, alterations in key proteins involved in insulin signaling have been also implicated in AD, among which GSK-3β, is also one of the important kinases for the phosphorylation of the microtubule-associated protein tau (tau), one of the pathological hallmarks of AD. The goal of this study is to determine the role of systemic insulin resistance in the pathophysiology of AD by testing the hypothesis that functional tau is important for peripheral insulin sensitivity, and its deletion or loss-of-function promotes peripheral insulin resistance.Primary hepatocytes were isolated from transgenic mouse models (P301L, tau KO), and wild type mice (C57BL/6), and their insulin sensitivity was assessed by an insulin challenge, using biochemical analysis of insulin signaling markers, and glucose uptake assays. To confirm the involvement of tau, we treated wild type hepatocytes with tau aggregates and investigated their effect on insulin sensitivity.We found that tau deletion or loss-of-function promotes peripheral insulin resistance as seen by the inhibition of insulin signaling proteins and the reduction of glucose uptake into primary hepatocytes isolated from tau KO and P301L mice, respectively. We also found that sub-toxic exposure of wild-type primary hepatocytes to tau aggregates resulted in inhibition of insulin signaling and glucose uptake, in a dose-dependent manner.This is the first study testing the potential role of tau in peripheral insulin resistance at the cellular level using multiple mouse models. Our findings suggest that functional tau is required for insulin sensitivity, therefore, any loss-of-function by mutations, aggregation or deletion would result in insulin resistance.