Mammalian target of rapamycin at the crossroad between Alzheimer’s disease and diabetes

Abstract

Accumulating evidence suggests that Alzheimer’s disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer’s disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer’s disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer’s disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161–1168, 1995; Leibson et al, Am J Epidemiol 145(4):301–308, 1997; Ott et al, Neurology 53(9):1937–1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s–291s, 2003; Janson et al. Diabetes 53(2):474–481, 2004; Ristow M, J Mol Med (Berl) 82(8):510–529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103–109, 2007; Ohara et al, Neurology 77(12):1126–1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer’s disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161–1168, 1995; Leibson et al, Am J Epidemiol 145(4):301–308, 1997; Ott et al. Neurology 53(9):1937–1942, 1999; Ohara et al, Neurology 77(12):1126–1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221–226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520–527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer’s disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167–1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897–3906, 2004; Kapahi et al, Curr Biol 14(10):885–890, 2004; Kaeberlein et al, Science 310(5751):1193–1196, 2005; Powers et al, Genes Dev 20(2):174–184, 2006; Harrison et al, Nature 460(7253):392–395, 2009; Selman et al, Science 326(5949):140–144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580–589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer’s disease and link to type 2 diabetes.