Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology

Abstract

High sugar consumption and diabetes increase the risk of developing Alzheimer's disease (AD) by unknown mechanisms. Using an animal model of AD, here we show that high sucrose intake induces obesity with changes in central and peripheral insulin signaling. These pre-diabetic changes are associated with an increase in amyloid-β production and deposition. Moreover, high sucrose ingestion exacerbates tau phosphorylation by increasing Cdk5 activity. Mechanistically, the sucrose-mediated increase in AD-like pathology results from hyperactive mammalian target of rapamycin (mTOR), a key nutrient sensor important in regulating energy homeostasis. Specifically, we show that rapamycin, an mTOR inhibitor, prevents the detrimental effects of sucrose in the brain without altering changes in peripheral insulin resistance. Overall, our data suggest that high sucrose intake and dysregulated insulin signaling, which are known to contribute to the occurrence of diabetes, increase the risk of developing AD by upregulating brain mTOR signaling. Therefore, early interventions to modulate mTOR activity in individuals at high risk of developing diabetes may decrease their AD susceptibility.

Introduction

Alzheimer's disease (AD) is an untreatable neurodegenerative disorder currently affecting more than 5 million Americans. The vast majority of AD cases are sporadic and of unknown etiology; nevertheless, epidemiologic studies have provided crucial insight into disease risk factors (Mayeux and Stern, 2012). Growing evidence shows that certain lifestyle choices, such as a high sugar or high fat diet, increase the risk of developing AD (Biessels et al., 2006). The Rotterdam study, a historic prospective population-based longitudinal study, identified that diabetes alone increases the risk of developing AD by ∼2-fold (Ott et al., 1999); this finding has been widely confirmed (reviewed by Sims-Robinson et al., 2010). Treating midlife health conditions known to increase the risk for developing AD, such as diabetes, may provide an opportunity for managing the projected increase in AD incidence.

Clinically, type 2 diabetic (T2D), metabolic syndrome and AD patients share many common pathophysiological features. These include hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia and inflammation; these traits reportedly correlate with attention and memory deficits (Jones et al., 2009). Mounting evidence suggests that insulin resistance and concomitant elevated blood glucose is a key metabolic dysfunction contributing to AD (reviewed by Cholerton et al., 2013). Namely, recent studies have reported evidence for insulin resistance in AD brains independent of the patients' diabetic status (e.g., Talbot et al., 2012). Additionally, preliminary results from an ongoing clinical study have revealed that T2D patients taking the insulin sensitizing drug, metformin, were less likely to develop AD then T2D patients taking other anti-diabetic medications (ClinicalTrials.gov Identifier: NCT01595646).

Neuropathologically, the AD brain is characterized by the accumulation of plaques, comprised mainly of amyloid-β (Aβ), and neurofibrillary tangles that are largely formed of hyperphosphorylated protein tau (Querfurth and LaFerla, 2010). Notably, patients with T2D have increased levels of hyperphosphorylated tau in their brains (Liu et al., 2009), further strengthening the link between diabetes and AD. The use of AD mouse models with either genetically or chemically induced-diabetes have also reported a link between diabetes and AD pathologies (Jolivalt et al., 2010, Ke et al., 2009, Plaschke et al., 2010, Takeda et al., 2010). For example, inducing type I diabetes by streptozotocin exacerbated the development of neurofibrillary tangles in a mouse model overexpressing mutant human tau (Ke et al., 2009). Similarly, induction of experimental diabetes with streptozotocin or analogous drugs increased Aβ and tau levels in wild-type mice and rabbits (Bitel et al., 2012, Ke et al., 2009). Collectively, studies provide compelling evidence that these prevalent age-associated diseases share alterations in common molecular pathways associated with glucose metabolism. However, the molecular mechanisms underlying the link between abnormal glucose homeostasis and AD remain to be elucidated.

Mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in maintaining energy homeostasis in the brain and other tissue types (Mannaa et al., 2013). As an energy sensor, mTOR regulates numerous cellular pathways including protein translation, cell growth, and proliferation. To modulate insulin signaling in times of high nutrient exposure, mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signaling (Wullschleger et al., 2006). However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2D (Saha et al., 2011). mTOR hyperactivity is also found in AD brains and in AD mouse models (Caccamo et al., 2010, Caccamo et al., 2011, Oddo, 2012, Pei and Hugon, 2008). We, and others, have shown that restoring mTOR activity using an mTOR inhibitor, rapamycin, mitigates AD-associated pathology and cognitive deficits (Caccamo et al., 2010, Majumder et al., 2011, Majumder et al., 2012, Spilman et al., 2010). As mTOR hyperactivity is common to both diabetes and AD, here, we explored the role of mTOR signaling as a molecular link between these two age-related diseases.