Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes

Abstract

Type 2 diabetes is increasingly recognized as a risk factor for Alzheimer's disease, but the underlying mechanisms remain poorly understood. Hyperphosphorylation of the microtubule-associated protein tau has been reported in rodent models of diabetes, including db/db mice, which exhibit insulin resistance and chronically elevated glucocorticoids due to leptin receptor insufficiency. In this report, we investigated endocrine mechanisms for hippocampal tau phosphorylation in db/db and wild-type mice. By separately manipulating peripheral and intrahippocampal corticosterone levels, we determined that hippocampal corticosteroid exposure promotes tau phosphorylation and activates glycogen synthase kinase 3β (GSK3β). Subsequent experiments in hippocampal slice preparations revealed evidence for a nongenomic interaction between glucocorticoids and GSK3β. To examine whether GSK3β activation mediates tau phosphorylation and impairs memory in diabetes, db/db and wild-type mice received intrahippocampal infusions of TDZD-8, a non-ATP competitive thiadiazolidinone inhibitor of GSK3β. Intrahippocampal TDZD-8 blocked tau hyperphosphorylation and normalized hippocampus-dependent memory in db/db mice, suggesting that pathological synergy between diabetes and Alzheimer's disease may involve glucocorticoid-mediated activation of GSK3β.

Introduction

Insulin-resistant diabetes is characterized by increases in circulating glucose and insulin levels, leading to reduced sensitivity to insulin among multiple somatic tissues including the brain. This condition arises from obesity, sedentary lifestyle, and genetic predisposition (Lazar, 2005). Age is also a risk factor for insulin resistance, with older adults developing type 2 diabetes at a higher rate than middle-aged or younger populations (DeFronzo, 1981). Aging is often accompanied by cognitive decline, specifically on tasks that recruit the hippocampus and associated cortical structures (Burke and Barnes, 2010). Susceptibility to cognitive decline is greater among insulin-resistant individuals (Ott et al., 1996, Velayudhan et al., 2010). Insulin resistance is associated with cognitive impairment among middle aged (Sandeep et al., 2004) and aged individuals without dementia (Convit et al., 2003, Reynolds et al., 2010). Changes in brain structure in insulin-resistant diabetes occur within temporal lobe circuits that are also sensitive to aging and Alzheimer's disease (AD; Bishop et al., 2010). Individuals with insulin-resistant diabetes exhibit hippocampal atrophy (Bruehl et al., 2009, Rasgon et al., 2011, Wu et al., 2008), and impairment of resting-state connectivity between the hippocampus and neocortical regions implicated in cognitive function (Zhou et al., 2010). Taken together with behavioral evidence that diabetes has a negative impact on cognition, the neuroimaging data suggest that similar negative outcomes occur during diabetes and brain aging.

Tangles composed of hyperphosphorylated tau protein are a major clinical hallmark of AD, the most common form of age-related dementia (Wang and Mandelkow, 2016). Individuals with type 2 diabetes are at increased risk for developing dementia, including AD (Biessels and Reagan, 2015), but the mechanisms underlying this increased susceptibility are not yet fully understood. In 2 separate studies by independent groups, analysis of tau phosphorylation in human brain samples from individuals with AD, diabetes, or both conditions revealed that diabetes exacerbates tau pathology (Liu et al., 2011, Valente et al., 2010). Changes in glucocorticoid levels and rhythmicity are a shared feature in rodent models of AD (Baglietto-Vargas et al., 2013, Green et al., 2006), and rodent models of type 2 diabetes (Stranahan et al., 2008). Lowering corticosterone levels reduces plaque burden and tau pathology in a triple-transgenic mouse model of AD (Green et al., 2006). Similar commonalities are evident in humans, where the inhibition of cortisol synthesis or bioactivity attenuates memory deficits in aged individuals and middle-aged diabetics (Lupien et al., 2005, Sandeep et al., 2004). These findings point to a possible mechanistic relationship between glucocorticoids and AD pathology in diabetes.

Leptin receptor–deficient (db/db) mice exhibit insulin resistance and hyperglycemia (Hummel et al., 1966), as well as increases in hippocampal tau phosphorylation and activation of glycogen synthase kinase 3β, a prominent tau kinase (GSK3β; Kim et al., 2009). db/db mice also exhibit elevated levels of corticosterone (Stranahan et al., 2008, Takeshita et al., 2000), but the potential relationship between elevated glucocorticoids and tau phosphorylation is yet to be explored in this model. To investigate possible associations between hippocampal corticosteroid exposure, GSK3β activation, and tau phosphorylation, we selectively manipulated hippocampal and peripheral corticosterone levels using intrahippocampal corticosterone infusions and pharmacological inhibition of adrenal steroidogenesis in db/db and wild-type (Wt) mice. After observing that increases in hippocampal corticosterone were necessary and sufficient for tau phosphorylation and GSK3β activation in these experiments, we investigated whether hippocampal glucocorticoids activate GSK3β via nongenomic mechanisms. To examine the role of GSK3β in tau phosphorylation and memory impairment in vivo, db/db and Wt mice received chronic intrahippocampal infusions of TDZD-8, a selective inhibitor of GSK3β. These experiments revealed that GSK3β-mediated tau phosphorylation underlies memory deficits and hippocampal tau phosphorylation in db/db mice. Additional work will be required to determine whether corticosteroids similarly promote tangle formation in htau mutant mice with diabetes, but the current findings provide a compelling rationale for further investigation into pathological synergy between diabetes and AD pathology.