Bidirectional interactions between diabetes and Alzheimer's disease

Neurochemistry International xxx (2017) 1e7

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Bidirectional interactions between diabetes and Alzheimer's disease Mitsuru Shinohara, Naoyuki Sato* Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430, Morioka, Obu, Aichi 474-8511, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 October 2016 Received in revised form 24 April 2017 Accepted 27 April 2017 Available online xxx

Clinical studies have indicated that diabetes is associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanisms underlying this association have not been fully elucidated. Diabetes causes neurodegeneration by inducing changes in vascular function and structure, glucose metabolism, and insulin signaling, as well as by modifying b amyloid (Ab)/tau metabolisms. In turn, AD influences systemic glucose metabolism by inducing behavioral changes, memory disturbances, hypothalamic dysfunction, frailty and possibly plasma/peripheral Ab level changes. Hypoglycemia, one of the major conditions encountered during the treatment of patients with diabetes, may also contribute to neurodegeneration. Through this vicious circle, diabetes and AD may cooperate to cause neurodegeneration. Various molecular, cellular, inter-organ, physical and clinical factors might contribute to the bidirectional interactions between diabetes and AD. Explorations of a key factor that underlies the bidirectional interactions, “Factor X”, could lead to the development of a potential therapeutic target for neurodegeneration. Factor X should fulfill the following equation: neurodegeneration equals Ab levels multiplied by Factor X. © 2017 Published by Elsevier Ltd.

Keywords: Diabetes Neurodegeneration Alzheimer's disease Ab Tau

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Diabetes and cognitive decline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Diabetes and brain atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Diabetes and cerebrovascular changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Diabetes, brain glucose metabolism and insulin signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Diabetes and AD pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.1. Ab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Tau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. AD and diabetes/glucose intolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Emerging evidence indicates that diabetes increases the risk of

* Corresponding author. E-mail address: [email protected] (N. Sato).

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Alzheimer's disease (AD) and neurodegeneration. However, the mechanisms by which diabetes modifies AD and the mechanisms underlying diabetes-associated peripheral neuropathy remain unclear (Sato and Morishita, 2013b, 2015). Insulin resistance in midlife is associated with neurodegeneration surrounding senile plaques (Matsuzaki et al., 2010), although retrospective studies have suggested that the magnitude of senile plaques is comparable between

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individuals with AD and diabetes and those with AD and without diabetes (Kalaria, 2009). Indeed, diabetes alters brain structure and function through various mechanisms, and its contributions to dementia vary among patients (Sato and Morishita, 2014). Furthermore, a dual effect has been observed. In addition to the effect of diabetes on AD, the effects of AD on diabetes and systemic metabolism may further contribute to the tendency of these two seemingly unrelated diseases to exacerbate one another. 2. Diabetes and neurodegeneration 2.1. Diabetes and cognitive decline Diabetes/impaired glucose tolerance is associated with mild cognitive impairment (MCI) (Roberts et al., 2014b) and with the progression to dementia in patients with MCI (Morris et al., 2014). Higher HbA1c levels are a risk factor for cognitive dysfunction (West et al., 2014) and for behavioral and psychological symptoms (Sakurai et al., 2014). Importantly, in a study of patients with familial AD harboring presenilin mutations, individuals with diabetes exhibited greater cognitive decline after the onset of AD (AguirreAcevedo et al., 2016). In patients with sporadic AD, patients with diabetes and substantial AD pathological changes exhibited lower cognitive function than patients with the pathological changes alone (Abner et al., 2016). Even among individuals without AD, cognitive function decreases more rapidly in patients with diabetes than in the controls (Weinstein et al., 2015; Redondo et al., 2016). In Holmes and colleagues' assessment of patients with diabetes who presented with hypoglycemia and hyperglycemia induced by an artificial insulin/glucose infusion, cognitive function was delayed when the patients’ glucose levels were altered (Holmes et al., 1983). According to observational studies, the use of anti-diabetic treatments is associated with a reduced risk of dementia (Heneka et al., 2015) (Ng et al., 2014), but other studies did not report similar observations (Moore et al., 2013). In the randomized Memory in Diabetes (MIND) sub-study of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, intensive glycemic control had no effect on cognitive function (Launer et al., 2011) (Strachan and Price, 2014). Intensive treatment increases the incidence of hypoglycemia (McCoy et al., 2016). Indeed, hypoglycemia is associated with cognitive impairment and dementia in elderly patients with diabetes (Whitmer et al., 2009; Yaffe et al., 2013; Pilotto et al., 2014). Therefore, diabetes treatments are considered to prevent hyperglycemia and hypoglycemia, improve cognitive performance and aid in preventing dementia. 2.2. Diabetes and brain atrophy Diabetes reduces brain volume (Sato and Morishita, 2014), including the volumes of the hippocampus (Kerti et al., 2013; Moran et al., 2013; Roberts et al., 2014b; Hirabayashi et al., 2016), gray matter (Garcia-Casares et al., 2014; Li et al., 2016) and white matter (Moran et al., 2013). Gray matter loss occurs in the frontal and temporal lobes and in the anterior cingulate cortex (Moran et al., 2013; Garcia-Casares et al., 2014; Roberts et al., 2014b; Erus et al., 2015), whereas white matter loss is also observed in the adjacent regions (Moran et al., 2013). Even in young adults, hyperglycemia is associated with brain atrophy (Weinstein et al., 2015). In animal models, neurodegeneration has been shown to be caused by the disturbance of glucose metabolism with substantial Ab levels in mice overexpressing mutant amyloid precursor protein (APP) crossed with ob/ob mice (Takeda et al., 2010). Moreover, a high-fat diet (Thiebaud et al., 2014), glucose transporter 1 (GLUT1) deficiency (Winkler et al., 2015), over-activation of the energy sensor AMP-activated protein kinase (AMPK) (Mairet-Coello

et al., 2013), and disruption of mammalian target of rapamycin (mTOR) signaling (Perluigi et al., 2015) have been shown to cause neurodegeneration. 2.3. Diabetes and cerebrovascular changes Diabetes increases vascular changes in the brain, heart, kidney and other organs. Vascular changes are concomitantly observed more frequently in the brains of patients with AD and diabetes than in patients with AD without diabetes (Kalaria, 2009). Compared to non-diabetes conditions, diabetes increases cerebral infarct volumes by more than 2-fold (Tanizaki et al., 2000; Arvanitakis et al., 2006; Roberts et al., 2011). Diabetes increases atherosclerosis in the brain by inducing insulin resistance and hyperglycemia (Schmidt et al., 1995; Vicent et al., 2003; Piga et al., 2007). Insulin resistance reduces nitric oxide production (Vicent et al., 2003), which alters the blood vessel reflex and increases the levels of adhesion molecules, which recruit monocytes to the vessel wall. Monocytes penetrate deep into the blood vessel wall and cause inflammation, resulting in arteriosclerosis. Advanced glycation end-products (Schmidt et al., 1995) or high glucose levels (Piga et al., 2007) increase the expression of vascular cell adhesion molecule-1 (VCAM1) in endothelial cells and subsequent inflammation and reduce NO production to exacerbate arteriosclerosis. Moreover, half of patients with diabetes are hypertensive (Sowers et al., 2001; Sowers, 2013), which accelerates vascular injury in the brain (Bouchi et al., 2010). 2.4. Diabetes, brain glucose metabolism and insulin signaling In humans, diabetes/hyperglycemia are associated with brain hypometabolism (Roberts et al., 2014a; Ishibashi et al., 2016; Li et al., 2016). Changes in the distribution pattern of [18F]-fluorodeoxyglucose (F-FDG) depend on the plasma glucose levels, and an AD-like pattern can appear in patients with hyperglycemia (Roberts et al., 2014a; Ishibashi et al., 2016). In an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, whole brain F-FDG uptake was lower in patients with MCI and diabetes than in patients with MCI without diabetes (Li et al., 2016), indicating that diabetes modifies brain glucose metabolism in the pre-dementia state. Insulin signaling also occurs in the brain (Sato et al., 2011). Brain insulin resistance has been reported in patients with AD (Talbot et al., 2012) and in animal models of diabetes (Takeda et al., 2010; Sato et al., 2011; Morales-Corraliza et al., 2016; Sajan et al., 2016). The expression of insulin-like growth factor-1 (IGF1)-binding protein, an inhibitor that binds IGF1, is increased in patients with peripheral diabetic neuropathy, and inhibition of IGF1 by overexpressing IGF1-binding protein in mice resulted in the development of motor axonopathy and sensory deficits (Rauskolb et al., 2016), indicating that the dysregulation of insulin/IGF signaling might also contribute to CNS neurodegeneration induced by diabetes. The molecular mechanism underlying the link between insulin signaling and neurodegeneration warrants further study. 2.5. Diabetes and AD pathology 2.5.1. Ab Diabetes/hyperglycemia modify Ab accumulation in the brains of wild type animals (Sparks et al., 1994) and animal models of AD (Refolo et al., 2000; Ho et al., 2004; Takeda et al., 2010). Hyperglycemia may increase Ab production by increasing the synaptic release of Ab (Macauley et al., 2015) or modulating APP processing and metabolism (Son et al., 2012) through molecules such as beta secretase-1 (BACE1) (Guglielmotto et al., 2012), glycogen synthase kinase-3b (GSK3b) (Phiel et al., 2003; Sereno et al., 2009; Sofola et al., 2010; Jaworski et al., 2011), or insulin-degrading enzymes

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Table 1 Bidirectional interactions between diabetes and Alzheimer's disease (AD) in humans and animal models. Humans

Animal models

Diabetes and AD Vascular changes Increased (Arvanitakis et al., 2006; Kalaria, 2009) Insulin signaling Decreased (Talbot et al., 2012) Glucose metabolism Treatments (hypoglycemia) Ab/Tau

AD and diabetes/ systemic glucose metabolism

Behavioral changes and Memory disturbances Hypothalamus Plasma/ peripheral Ab Frailty/ sarcopenia

Decreased (Roberts et al., 2011, 2014a, 2014b)

Increased (Takeda et al., 2009, 2010, 2012) Increased (Sajan et al., 2016) or decreased (Takeda et al., 2009, 2010, 2012) e

Increased risk for dementia (Yaffe et al., 2013)

e

Decreased Ab levels (Kalaria, 2009), or unchanged Ab levels (Arvanitakis et al., 2006, Kalaria, 2009, Roberts et al., 2011, 2014a, 2014b; Pruzin et al., 2016)/increased phospho-Tau levels (Starks et al., 2015) or unchanged phospho-Tau levels (Arvanitakis et al., 2006; Kalaria, 2009, Pruzin et al., 2016)

Increased Ab levels (Sparks et al., 1994; Refolo et al.2000; Ho et al., 2004; Macauley et al., 2015; Sajan et al., 2016)/increased phospho-Tau levels (Ke et al.2009; Kim et al., 2009; Qu et al., 2011; El Khoury et al., 2016; Guo et al., 2016; Morales-Corraliza et al., 2016; Sajan et al., 2016) or unchanged Tau pathology (Gratuze et al., 2016) e e

Increased (Burns et al., 1990; Shinagawa et al., 2016)

Impaired (van de Nes et al., 1998) Increased plasma Ab (Takeda et al., 2009, 2010, 2012), pancreas Ab (Miklossy et al., 2008) and skeletal muscle Ab levels (Roher et al., 2009) Common (Oosterveld et al., 2014)

Impaired (Clarke et al., 2015) Increased plasma Ab levels (Takeda et al., 2009, 2010, 2012; Zhang et al., 2013) e

Fig. 1. Bidirectional interactions between diabetes and Alzheimer's disease (AD) and a key factor that underlies the interactions, “Factor X”. A, Various mechanisms contributing to the bidirectional interactions between diabetes and AD, as well as a key factor that underlies the interactions. B, Equation: neurodegeneration equals Ab levels multiplied by Factor X.

(IDE) (Vekrellis et al., 2000). However, firm evidence showing that diabetes increases Ab deposition in humans is not currently available (Tomita et al., 2013; Roberts et al., 2014a). Rather, hyperglycemia and Ab may cooperate to induce neurodegeneration (Akhtar et al., 2016). 2.5.2. Tau In humans, insulin resistance is associated with neurodegeneration, tau phosphorylation surrounding senile plaques (Matsuzaki et al., 2010), and higher tau levels in the cerebrospinal

fluid (CSF) (Starks et al., 2015). In turn, the CSF tau levels predict changes in neurodegeneration and brain glucose metabolism (Dowling et al., 2015). Moreover, tau phosphorylation at the sites implicated in AD is increased in the brains of subjects with diabetes (Liu et al., 2009). Tau phosphorylation is increased in animal models of both type 1 (Clodfelder-Miller et al., 2006; Jolivalt et al., 2008; Ke et al., 2009; Qu et al., 2011; Morales-Corraliza et al., 2016) and type 2 diabetes (Kim et al., 2009; El Khoury et al., 2016; Guo et al., 2016), potentially through the deregulation of c-Jun N-terminal kinase (JNK), AMPK, and protein phosphatase 2A (PP2A)

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(Mairet-Coello et al., 2013; El Khoury et al., 2016). However, according to retrospective human neuropathological studies, the number of neurofibrillary tangles (NFTs) in the brain at autopsy did not differ between patients with AD and diabetes and those with AD and without diabetes (Arvanitakis et al., 2006; Kalaria, 2009; Abner et al., 2016; Pruzin et al., 2016), and diabetes/hyperglycemia did not affect tau pathogenesis in human tau transgenic mice (Gratuze et al., 2016). Based on these findings, diabetes may mediate Ab-induced tau phosphorylation in early stages but does not exacerbate NFTs at later stages. 2.6. AD and diabetes/glucose intolerance Interestingly, patients with AD have also been reported to present glucose intolerance (Bucht et al., 1983; Meneilly and Hill, 1993; Janson et al., 2004). However, a causal relationship was not determined in these clinical studies. Studies using animal models have effectively shown an effect of AD on peripheral glucose metabolism (Takeda et al., 2010; Sato et al., 2011; Clarke et al., 2015; Ruiz et al., 2016). Although further evidence is needed to confirm these findings, studies investigating the mechanisms by which AD affects the diabetic phenotype are intriguing. Several potential mechanisms have been proposed. First, behavioral changes induced by neurodegeneration in the hippocampus and/or the frontal lobe may be involved in the phenotype. As described above, diabetes causes neurodegeneration in the frontal lobe, hippocampus and white matter and leads to subsequent behavioral changes and memory disturbances. Binge-eating, an eating disorder characterized by recurrent episodes of eating large quantities of food, is also sometimes observed in patients with AD (Burns et al., 1990) and eatingrelated problems, such as overeating, are common in patients with dementia, including AD (Shinagawa et al., 2016). Therefore, these behavioral changes might contribute to the modifications of systemic metabolism, although further studies are required. Second, Ab deposition and tau phosphorylation in the hypothalamus may contribute to an impairment of the central control of peripheral glucose metabolism in patients with AD (van de Nes et al., 1998). In support of these findings, an intracerebroventricular infusion of Ab into the hypothalamus induced peripheral metabolic deregulation (Clarke et al., 2015). Third, plasma/peripheral Ab levels might also mediate peripheral insulin resistance. Plasma Ab levels increase after glucose loading in an AD mouse model and patients with AD, although to a lesser extent (Takeda et al., 2009, 2012; Sato and Morishita, 2013a). Plasma Ab levels also play a role in impaired glucose tolerance and hepatic insulin signaling in AD mice (Zhang et al., 2013). In addition, Ab accumulation also occurs in the pancreas (Miklossy et al., 2008) and skeletal muscle (Roher et al., 2009) and may contribute to the effect on peripheral glucose metabolism. Fourth, frailty is common in patients with AD (Oosterveld et al., 2014). Frailty/sarcopenia causes insulin resistance in skeletal muscle (Cleasby et al., 2016), mediating the link between AD and diabetes. Potential strategies towards identifying Factor X that underlies the bidirectional interactions between diabetes and AD. As shown in a recent large randomized controlled trial, a 2-year multidisciplinary intervention, including exercise and diet, improves or maintains cognitive function in at-risk elderly people (Ngandu et al., 2015). Breaking the vicious circle between diabetes and neurodegeneration might contribute to the prevention of dementia. As discussed in this review, various molecular, cellular, inter-organ, physical and clinical factors might contribute to the bidirectional interactions between diabetes and AD (Table 1). Each factor may be a therapeutic target, as has been discussed previously (Sato and Morishita, 2013b). Briefly, vascular and metabolic components in both short- and long-term should be taken into account

for preventing dementia, although the contributions of these components vary among individuals. For vasculature, amelioration of functional vascular impairment and prevention of irreversible vascular events are needed. For metabolic components, appropriate anti-diabetic therapy is required to avoid hypoglycemia, although vascular complication also should be prevented. Exploring a key factor (Factor X) that underlies these bidirectional interactions could lead to the development of a potential therapeutic target for neurodegeneration (Fig. 1). Factor X is supposed to be a key molecule/pathway that links Ab to neurodegeneration, and it also governs a vicious cycle between AD and diabetes. As such, the level of neurodegeneration based on clinical evidence should equal Ab levels multiplied by Factor X. In addition, evidence from cellular and animal models would be necessary to determine Factor X, e.g. if genetic deletion or pharmacological blockade of a specific pathway or gene in APP and/or APP mice with diabetes led to recovery from cognitive deterioration, neurodegeneration and/or AD-accelerated diabetes, it could be a Factor X. It would not be a simple task to identify Factor X but it should be a worthwhile endeavor given that it could lead to a novel target for the development of effective pharmaceuticals for dementia and diabetes that would benefit millions of patients suffering from these devastating diseases. Acknowledgments This work was supported in part by the Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology (28-45); Grants-in-Aid from Japan Promotion of Science; the Japanese Ministry of Education, Culture, Sports, Science and Technology and the Japan Science and Technology Agency (MEXT26293167, MEXT15K15272 & MEXT17H04154); a Takeda Science Foundation Research Encouragement Grant; a SENSHIN Medical Research Foundation Research Grant; a Novartis Foundation for Gerontological Research Award; an Annual Research Award Grant from the Japanese Society of Anti-aging Medicine; and a Takeda Medical Research Foundation Research Grant. Abbreviations Ab b amyloid CNS central nervous system AD Alzheimer's disease MCI mild cognitive impairment HbA1c hemoglobin A1c ACCORD-MIND The Memory in Diabetes sub-study of the Action to Control Cardiovascular Risk in Diabetes study ADNI Alzheimer's Disease Neuroimaging Initiative APP amyloid precursor protein GLUT1 glucose transporter 1 AMPK AMP-activated protein kinase mTOR mammalian target of rapamycin VCAM-1 vascular cell adhesion molecule-1 NO nitric oxide eNOS endothelial nitric oxide synthase F-FDG [18F]-fluorodeoxyglucose IRS1 insulin receptor substrate-1 IGF1 insulin-like growth factor-1 IGFBP5 IGF-binding protein 5 NFTs neurofibrillary tangles JNK c-Jun N-terminal kinase PP2A protein phosphatase 2A PDX1 pancreatic and duodenal homeobox 1 BACE1 beta secretase-1 GSK3b glycogen synthase kinase-3b

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IDE PS1 GLP1

insulin-degrading enzymes presenilin1 glucagon-like peptide-1

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