J Neural Transm DOI 10.1007/s00702-013-1147-1
NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Mechanisms of action of brain insulin against neurodegenerative diseases Mahesh Ramalingam • Sung-Jin Kim
Received: 26 June 2013 / Accepted: 17 December 2013 Ó Springer-Verlag Wien 2014
Abstract Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.
M. Ramalingam S.-J. Kim (&) Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University, 26, Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea e-mail: [email protected]
Keywords Insulin Neurodegenerative disease Brain Neuroprotection Brain signaling pathways
Introduction The brain consumes large amounts of oxygen to generate the adenosine triphosphate (ATP) and phosphocreatine required for the maintenance of cellular functional homeostasis (Halliwell 2006). However, part of the oxygen is physiologically diverted to the generation of reactive oxygen species (ROS) (Floyd and Hensley 2002). Hence, most of the oxygen-derived reactive species are unstable, short-lived and react extremely quickly with other molecules (Ramalingam and Kim 2012). These excessive ROS in normal cells can initiate tissue damage to the destruction of cellular components, including lipids, proteins and DNA which can induce generation of secondary reactive species and ultimately lead to cell death in neurodegenerative diseases (NDDs) via apoptosis and necrosis (Ramalingam and Kim 2012). Incidences of NDDs are projected to increase considerably as a result of the growing aging population in the coming decades (Pangalos et al. 2007). However, a major challenge in neurodegenerative disease research is to identify disease-modifying strategies (Vazquez-Manrique et al. 2013). Each of the NDDs has its distinct ecological processes and differently affects brain regions, mitochondrial changes, though in varying degrees, suggesting the connection of disease pathology to the overall character of neurodegeneration (Ramalingam and Kim 2012; Du and Yan 2010). Hence, the study of NDDs including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS) is expected to shed light on the mechanisms that
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underlie neurodegeneration (Vazquez-Manrique et al. 2013). Increasing evidence suggests that insulin and insulin signaling mechanisms are critical for neuronal survival in the NDDs (Hoyer and Lannert 2007). Normal intracellular insulin signaling is putatively involved in several aspects of brain physiology (Plum et al. 2005), and alterations in this pathway have been consistently implicated in the etiology of NDDs (Hoyer and Lannert 2007). Therefore, biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. In this review, we focused on identifying the relationship of the insulin network to the brain as well as to determine the mechanisms through which insulin dysregulation promotes NDDs (Craft et al. 2013).
Insulin Insulin is a peptide hormone of 5.8 kDa molecular weight secreted from beta cells of the endocrine pancreas (Reaven 1997). It is composed of two peptide chains connected to each other by disulfide linkages (Steiner and Oyer 1967). Insulin was first identified in the early 1920s as the major hypoglycemic hormone, capable of restoring normal blood glucose levels by its effects on glucose metabolism in the liver, skeletal muscle and adipose tissue (Konrad et al. 2005). Thus, the physiological functions of insulin are shown in Fig. 1. Nevertheless, freshly secreted pancreatic insulin exerts direct hormonal effects on the liver, while the remainder enters the larger systemic plasma volume (Jones and Shojaee-Moradie 2002). Insulin secretion is subject to control by nutrients, hormonal, neural and pharmacological factors. Among these, glucose is by far the most important regulator of the machinery of insulin secretion (Gembal et al. 1992). Diabetes is a group of metabolic diseases characterized by deficits in insulin production (Type 1) or impairment of insulin sensitivity (Type 2) (Stranahan and Mattson 2010). Insulin resistance, a syndrome characterized by a diminished ability of insulin to perform its normal
Fig. 1 Physiological functions of insulin. Right-pointing arrows denote stimulation, and round-tip arrows inhibition
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physiological functions, is the main feature of type 2 diabetes and the key factor in the development of the metabolic syndrome (Medina-Gomez et al. 2005). The development of insulin resistance is closely correlated with immune cell infiltration and inflammation, with clear links between the development of obesity, type 2 diabetes mellitus and cardiovascular disease (Hotamisligil 2006). However, the more widespread development of insulin resistance has also been proposed to be mediated through mitochondrial dysfunction (Stark and Roden 2007). Insulin release is regulated in response to the levels of blood glucose or other nutrients and thus insulin stimulates anabolic pathways through the regulation of carbohydrate, lipid and protein metabolism while it inhibits catabolism of these fuel reserves (Lara-Castro and Garvey 2004). Approximately 50 % of the insulin reaching the liver is degraded without passing on to the general, systemic circulation to the other tissues of the body (Chap et al. 1987). In normal subjects, insulin is secreted briskly in response to a meal (Jones and Shojaee-Moradie 2002).
Insulin on macromolecule metabolism Circulating insulin levels during fasting are 5–20 % of those measured after a meal required to maintain the balance with counter-regulatory hormones to prevent ketoacidosis (Konrad et al. 2005). In carbohydrate metabolism, insulin stimulates rapid glucose uptake, storage, and utilization of glucose by almost all tissues of the body particularly the muscle, liver and adipose tissues (Oh 2013). Insulin activates the glucose storage as glycogen synthesis and decreases liver phosphorylase activity, but increases the activity of glucokinase (Lawrence and Roach 1997). Insulin also increases glycolysis and pentose pathways to increase glucose utilization but decreases gluconeogenesis by deactivating gluconeogenic enzymes (Hales 1971). Insulin also regulates lipid metabolism (Oh 2013). It is a key regulator of the interplay between glucose and fatty acid metabolism (Konrad et al. 2005). Insulin stimulates glucose uptake into adipose tissue cells which when converted to glycerol and/or fatty acids is used as substrate in the synthesis of triglyceride, a storage form of fat (Williamson 1989). Insulin decreases the breakdown and mobilization of fatty acids from triglycerides by inhibiting the activity of hormone-sensitive lipase whereas by activating lipoprotein lipase in the wall of capillary vessels near adipocytes, it increases fatty acid translocation into adipocytes and storage in the form of triglycerides (Williamson 1989). It has long been appreciated that insulin affects protein metabolism and growth (Oh 2013). A cellular protein breakdown is a tightly controlled and highly specific
Mechanisms of action of brain insulin
process including the lysosomal pathway, the calciumdependent protease pathway or the ubiquitin–proteasome path (Goldberg and St John 1976). Insulin stimulates protein synthesis and storage through increasing amino acid uptake, transcription and mRNA translation, whereas insulin inhibits breakdown of proteins by inhibiting proteolysis, gluconeogenesis and lysosome activity (Miers and Barrett 1998).
(de Moura et al. 2010). Herewith, insulin and insulin receptor (IR)-mediated signaling pathways (together with the inseparable insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R)) seem to play a crucial role in the regulation of central nervous system (CNS) metabolism, neuronal growth and differentiation, neuromodulation and neuroprotection (Duarte et al. 2012).
Insulin receptors (IRs) Insulin and the brain Insulin is widely known as a peripheral regulator of glucose transport and molecular metabolism in the adipocyte, muscle and liver cells (Schulingkamp et al. 2000; Oh 2013), which involve a complex crosstalk between peripheral nutritional and other hormonal signals (Duarte et al. 2013). However, it has earlier been considered that the brain was insulin-independent over a long time (Oh 2013), but it is now known that little or no insulin is produced in the brain itself (particularly in pyramidal neurons, e.g., from hippocampus, prefrontal cortex, entorhinal cortex, and olfactory bulb, but not in glial cells) (Hoyer 2003), being then released by exocytosis (Clarke et al. 1986). Insulin crosses the blood–brain barrier (BBB) and enters the brain via a receptor-mediated active transport system (Baura et al. 1993) and thus may also be synthesized by neurons in the brain (Devaskar et al. 1994). Interestingly, it plays a very important role in the regulation of peripheral and central glucose metabolism, feeding behavior, neurotransmission, learning and memory, maintenance of neural functions, and is neuroprotective (Plum et al. 2005; Zhao and Alkon 2001; Gerozissis 2008). This is consistent with reports that insulin is highly enriched in the brain cortex, olfactory bulb, hippocampus, hypothalamus, and amygdala (Havrankova et al. 1978). The findings strongly suggest that brain insulin signaling is required for a normal mitochondrial function and metabolism (Cheng et al. 2009) that could be helpful to maintain the central regulation of energy balance in the brain and to avoid the development of neurodegenerative diseases associated with impaired learning, memory and age-related diseases (Correia et al. 2011; Talbot et al. 2012; Muller et al. 2013). Moreover, poorly controlled diabetes has deleterious consequences on multiple organ systems, including the brain (Stranahan and Mattson 2010). A rapid increase or decrease in glucose level potentiates ROS toxicity as well as contributes to neural injury (Dasgupta et al. 2013). Neuronal cells in the brain are highly sensitive to oxidative stress due to their large dependence on oxidative phosphorylation for energy as compared to other cells (Dasgupta et al. 2013). This creates a potential oxidative stressful condition in the brain even in normal situations
Insulin actions are mediated through the insulin receptor (IR). The IR is a membrane protein of tyrosine kinase receptor family comprised of two alpha and two beta subunits that is widely expressed in the brain (Lee et al. 2011; Nemoto et al. 2010) with relatively high density located in the olfactory bulbs, hypothalamus and hippocampus (Havrankova et al. 1978; Unger et al. 1989). It has been linked to a wide variety of physiological functions including the energy homeostasis, food intake and body weight, fertility and reproduction, learning and memory, as well as aging (Lee et al. 2011). Brain IRs are present in particularly high concentrations in neurons, and at much lower levels in glial cells (Schwartz et al. 1992; Unger et al. 1989) and the neuronal IR signal transduction is similar to that of peripheral IRs (Salkovic-Petrisic et al. 2006).
Insulin-like growth factor-1 (IGF-1) Insulin-like growth factor-1 (IGF-1) is a basic polypeptide that is widely expressed in the CNS (Joseph D’Ercole and Ye 2008). IGF-1 belongs to the insulin-like growth factor (IGF) family of proteins, to which the agonists IGF1 and IGF2, the receptors IGF1R and IGF2R, and several IGFbinding proteins (IGFBP1-7) belong (Fernandez and Torres-Aleman 2012; Duan 2002; Bondy and Cheng 2004). Both IGF1 and IGF2 signal through the IGF1R leading to the growth and metabolic effects via the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway (Suh et al. 2013). IGF-1 is a crucial factor involved in normal cognitive function and successful aging (Denley et al. 2005; Carson et al. 1993; Camacho-Hubner et al. 2002). Impaired hippocampal insulin/IGF-1 action could result in cognition deficit and subsequent neuronal apoptosis (Li et al. 2002). It also provides effective protection against loss of dopaminergic neurons (Guan et al. 2000; Quesada et al. 2008; Offen et al. 2001). Increased serum IGF-1 levels in early PD may reflect a compensatory effort to protect dopaminergic neurons from degeneration and/or may be as a result of an increased dopamine turnover as compensation for already diminished dopaminergic function (Picillo et al. 2013).
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Insulin receptor substrates (IRSs) Insulin receptor substrates (IRS) are signaling adaptor proteins that function as intermediates of activated cell surface receptors, most notably for the IR and IGF-1R (Metz and Houghton 2011). Binding of insulin to the IR and IGF-1R activates the tyrosine kinase domain on the IR and IGF-1R, which results in tyrosine phosphorylation of multiple insulin receptor substrates (IRSs) (Holscher et al. 2008; Nemoto et al. 2010; Takeda et al. 2011). Phosphorylated IRS proteins activate several downstream signaling pathways, including PI3K/Akt/GSK-3 and Ras/MEK/ERK (Nemoto et al. 2010). Thus, the Ras/MEK/ERK pathway activates the downstream target cAMP response element binding protein (CREB), which is involved in long-term memory formation in the brain (Tully et al. 2003; Liu et al. 2013a).
Cerebral insulin resistance Insulin resistance is a common pathological state in which target cells failed to respond to ordinary levels of circulating insulin (Kahn and Flier 2000). It is generally agreed that insulin located within the brain is mostly of pancreatic origin, having passed through the BBB. Although there is little debate about the amount of insulin that is produced de novo within the CNS (Umegaki 2013). Insulin can reach high levels in the brain (Schechter et al. 1992; LeRoith 1983) and exert long-term neuronal trophic effects (Schulingkamp et al. 2000). Insulin resistance occurs when the cells (insulin receptors) are progressively unable to have a proper insulin response resulting in an inadequate entry of glucose in the cells (Tremblay-Mercier 2012). Insulin resistance is either a precursor or key component of numerous modern major health problems of industrialized societies, including obesity, metabolic syndrome, cardiovascular disorders, nonalcoholic fatty liver disease, depression, Alzheimer’s disease, asthma, some cancers and aging (Ning et al. 2011). Acute elevations of plasma insulin levels have been found to correlate with cerebro-spinal fluid (CSF) insulin concentrations in healthy, normal weight humans (Yanagita et al. 2013). Cerebral insulin resistance is seen as the result of various mechanisms at different levels (Yanagita et al. 2013). In addition, the role of insulin signaling in the development of insulin resistance is more due to the direct effects of insulin on insulin-signaling components, including the IR itself (Shanik et al. 2008). Nevertheless, fats may be unable to induce insulin resistance without insulin (Ning et al. 2011). Thus, insulin signaling itself is a legitimate target for prevention and reversion of insulin resistance and its numerous associated major health problems (Ning et al. 2011).
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AD patients have an increased risk of hyperinsulinemia and hyperglycemia relative to healthy controls (Meneilly et al. 1993; Razay and Wilcock 1994). Restoration of insulin signaling by the proinsulin C-peptide prevents deleterious effects of type-1 diabetes in rats (Sima and Li 2005), while a comparison of type-2 diabetes versus type-1 diabetes in rats showed that neuronal loss, neurite degeneration, impaired amyloid precursor protein (APP) metabolism, increased hyperphosphorylated tau protein (P-Tau) and dysfunctional insulin/IGF-1 signaling were more severe in type-2 diabetes, probably as a result of insulin resistance (Li et al. 2007).
Insulin and neurodegenerative diseases Insulin acts as a neuropeptide in the brain to regulate food intake, body weight, mood, cognitive function, memory, neuronal survival and synaptic plasticity (Laron 2009; Stockhorst et al. 2004). To this extent, an increased understanding of the complexity of insulin signaling in the brain and the interactions between central and peripheral effects of insulin is desirable (Gerozissis 2008). Conversely, dysregulated insulin receptor signaling (e.g. insulin deficiency and insulin resistance) in the brain is involved in the neurodegenerative diseases (Yanagita et al. 2013). Therefore, altered or defective insulin action in the brain may cause or promote metabolic diseases such as obesity, diabetes or AD suggesting that central insulin resistance might not only be a consequence but also a starting point for the development of obesity and possibly of type-2 diabetes (Gerozissis 2008). Alzheimer’s disease (AD) AD is a neurodegenerative disorder that typically occurs late in life and is characterized by memory loss and cognitive impairment (Pandini et al. 2013) associated with progressive neuronal degeneration and the accumulation of neurofibrillary tangles and insoluble b-amyloid (Ab) plaques in the CNS (Pandini et al. 2013). Insulin performs important functions in brain regions involved in learning and memory (Zhao and Alkon 2001; Craft and Watson 2004). In addition to its typical metabolic effects, insulin also activates mechanisms relating to neuronal activity, including APP processing, Ab generation, and Tau protein phosphorylation as well as all major components of AD pathogenesis (Pandini et al. 2013). AD patients also have a reduced cerebro-spinal fluid to plasma insulin ratio (Craft et al. 1998). Hence, insulin signaling impairment leads to abnormal APP processing and Ab accumulation (Pandini et al. 2013). These studies suggest a possible role of impaired insulin action (i.e. insulin resistance and/or insulin deficiency) in the pathogenesis of AD (Pandini et al. 2013).
Mechanisms of action of brain insulin
Moreover, insulin resistance leads to accelerated lipolysis and increased free fatty acid levels, leading to higher and more prolonged post-prandial excursions of very low-density lipoprotein (VLDL) and other deleterious lipids (Craft et al. 2013). This tendency precedes Ab deposition in the brain (Burgess et al. 2006), and high fat feeding increases brain amyloid burden (Sechi 1999). Interestingly, intranasal insulin administration has an improving effect of learning and memory as well as a mood stabilizing effect in the patients with AD and healthy volunteers (Reger et al. 2006; Reger et al. 2008; Benedict et al. 2004; Benedict et al. 2007). Thus, insulin receptor signaling attracts attention as the molecular target for the treatment of cognitive and mood disorders (Yanagita et al. 2013). Parkinson’s disease (PD) PD is clinically characterized by cardinal motor symptoms including bradykinesia, rigidity, rest tremor and postural instability caused by the progressive loss of dopaminergic neurons in the substantia nigra (Braak et al. 2003). PD and type-2 diabetes mellitus may relate to abnormalities in a common pathway or indirectly as a consequence of chronic hyperglycemia or hyperinsulinemia (Aviles-Olmos et al. 2013). Neuropathological studies of patients with PD have shown that insulin receptors are densely represented on the dopaminergic neurons of the substantia nigra pars compacta (Unger et al. 1991) and loss of insulin receptor immunoreactivity and messenger RNA in the substantia nigra pars compacta of patients with PD coincides with loss of tyrosine hydroxylase messenger RNA (the rate-limiting enzyme in dopamine synthesis (Moroo et al. 1994; Takahashi et al. 1996). IGF-1 has been shown to provide effective protection against loss of dopaminergic neurons (Guan et al. 2000; Quesada et al. 2008; Offen et al. 2001). IGF-1 was found to relate to dopaminergic score (Picillo et al. 2013). Huntington’s disease (HD) HD is an autosomal dominantly inherited progressive neurodegenerative disorder that manifested in cognitive, psychiatric and motor symptoms (Zadori et al. 2011). Normoglycemic HD patients have been shown to have impaired insulin sensitivity and secretion (Lalic et al. 2008). HD patient examined had the smallest beta-cell area and lowest level of insulin mRNA (Bacos et al. 2008). Hence, reduced insulin signaling through reduced levels of IRS-2 or IGF-1 improves disease phenotypes in mouse models of HD (Sadagurski et al. 2011). Moreover, Rhes has also been shown to participate in Akt signaling through other mechanisms. Therefore, it not only interacts with Akt directly to enhance its phosphorylation by growth factors (Bang et al. 2012), but also allows for its
dephosphorylation with alternate cues (Harrison and Lahoste 2013). PI3K-Akt-mTOR signaling has a role in increasing neuronal size and dendritic complexity (Kumar et al. 2005).
Insulin on signaling pathways Under physiological condition, several ‘intrinsic’ downstream serine/threonine kinases in the insulin pathway such as Akt/PKB, mTOR, and ERK1 phosphorylate serine/ theronine residues of the IRS proteins and inhibit insulin signaling as a negative feedback regulation (De Hert et al. 2012). In neurons, the PI3K [ Akt [ GSK3beta [ BAD, FOXO, TOR and GLUTs pathways are clearly critical for survival signaling (Cole and Frautschy 2007). Thus, all of these pathways contribute to the hypothesis that increased insulin signaling in the brain would promote neuronal development and continued survival in vitro and in vivo (Cole and Frautschy 2007). Therefore, the proposed consequences of normal and impaired insulin signaling networks are diagrammatically represented in Figs. 2 and 3. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt/PKB) PI3K is a key anti-apoptotic effector in the growth factor signaling pathway (Hui et al. 2005). Akt/PKB, a 57-kDa protein-serine/threonine kinase expressed as Akt1 and Akt2 (Downward 1998), serves a key role in mediating the antiapoptotic actions of growth factors on cell (Datta et al. 1997) and plays an important role in neuronal protection (Hui et al. 2005). Stimulation of tyrosine kinase growth factor receptors activates PI3K, leading to Akt activation (Hui et al. 2005), further downstream, vesicular translocation of glucose transporter 4 (GLUT4) and activation of glucose transport (Le Marchand-Brustel et al. 1999). Previous studies clearly showed that insulin could effectively activate Akt in brain cells (Kim and Han 2005; Ramalingam and Kim 2009). Akt activation is correlated with phosphorylation of Thr-308 at its catalytic domain and of Ser-473 at the C terminus (Hui et al. 2005) and inactivates glycogen synthase kinase-3 (GSK-3b), Bad, and the forkhead transcription factors (Fort et al. 2010). Thus, much of insulin’s downstream signaling to affect metabolic events involves the activation of PI3K (Piwkowska et al. 2012). However, IGF-1 binding IGF-1R prevents neuronal death after transient forebrain ischemia in rats (Hui et al. 2005). Mitogen-activated protein kinases (MAPKs) The mitogen-activated protein kinases (MAPKs) are also sensitive to oxidative stress conditions, which entails an
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M. Ramalingam, S.-J. Kim Fig. 2 Diagrammatic representation of brain insulin signaling pathways. Rightpointing arrows denote stimulation, and round-tip arrows inhibition
Fig. 3 Diagrammatic representation of impaired brain insulin signaling pathways. Right-pointing arrows denote stimulation, and round-tip arrows inhibition
enhanced generation of hydrogen peroxide (H2O2) or peroxynitrite, resulting in their activation (Yin et al. 2012). c-Jun N-terminal kinase (JNK), a member of the MAPK family, is important in inducing neuronal death (Hui et al. 2005). The JNKs are encoded by three genes: JNK1, JNK2 and JNK3 (Hui et al. 2005). Activated JNK, in turn, phosphorylates a number of transcription factors, especially the c-Jun of the components of activator protein-1 (AP-1), and cellular proteins, particularly those associated with apoptosis (Manning and Davis 2003). In addition, JNK also plays a central role in the progression of insulin resistance; a likely mechanism that entails the phosphorylation of the IRS-1 at Ser307, leading to inhibition of the insulin-
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promoted tyrosine phosphorylation of IRS (Aguirre et al. 2000). Similarly, activated JNK specifically phosphorylates the N-terminal activation domain of the transcription factor c-Jun at serine 63 and 73 thereby increasing transcriptional activity of c-Jun (Minden et al. 1994). Brain ischemia promotes both the expression and phosphorylation on serine 63 of c-Jun (Guan et al. 2005). Therefore, the decrease in intracellular Ab stimulated by insulin in N2a murine neuroblastoma cells occurs via the MAPK pathway activation (Gasparini et al. 2001). Thus, the neuroprotective action of insulin is possibly by activating anti-apoptotic signaling of PI3K/Akt pathway and blocking the activation of JNK signaling (Kim and Han 2005; Hui et al. 2005).
Mechanisms of action of brain insulin
Forkhead box ‘Other’ (FOXO) proteins Forkhead box ‘Other’ (FOXO) proteins have emerged as an important targets of insulin and growth factor action (Barthel et al. 2005). Hence, they are able to integrate several types of external stimuli to regulate gene expression and modulate cell cycle arrest, apoptosis, autophagy, angiogenesis, differentiation, stress resistance, stem cell maintenance, glucogenesis and food intake (VazquezManrique et al. 2013). Insulin and IGF-1 both inhibit FOXOs by a mechanism that requires PI3K (Anton et al. 2007; Nakae et al. 1999; Rena et al. 1999), and 3-phosphoinositide-dependent protein kinase-1 (PDK1) (Rena et al. 2002). FOXO3a (forkhead box, class O, 3a) belongs to the family of mammalian FOXOs with a ubiquitous distribution and high expression in the brain (Furuyama et al. 2000), which are regulated by growth factor receptorinduced activation of the PI3K/Akt signaling pathway (Zhu et al. 2004). Activation of growth receptors, such as insulin, IGF-1 and nerve growth factor (NGF), activates PI3K and subsequently increases the production of PI3,4biphosphate and PI3,4,5-triphosphate, leading to phosphorylation and activation of Akt (Burgering and Coffer 1995). Therefore, activation of Akt by insulin/IGF-1 causes phosphorylation of FOXO1a on Thr24, Ser256 and Ser319 (Nakae et al. 1999; Rena et al. 1999) as well as FOXO3a at the threonine32, serine253 and serine315 sites (Brunet et al. 1999). Glycogen synthase kinase-3 (GSK-3)
a member of the phosphoinositol kinase-related kinase (PIKK) family of kinases and phosphorylates proteins on serine and threonine residues (Garelick and Kennedy 2011). Enhanced mTORC1 (functionally distinct complex of mTOR) function is mediated through activation of receptors for growth factors, hormones and cytokines (Garelick and Kennedy 2011). Moreover, binding of insulin to the IR recruits IRS and activates the catalytic subunit of PI3K, as well as generates the production of phosphatidylinositol (3,4,5)-triphosphate (PIP3). Thus, PI3K recruits 3-phosphoinositide-dependent kinase 1 (PDK1) to phosphorylate Akt which promotes cell growth and survival through its numerous targets (Scheid and Woodgett 2001). p70S6K The 70 kDa ribosomal protein S6 kinase, p70S6K, is one of the downstream effectors of the PI3K/Akt/mTOR pathway which plays a key role in insulin-stimulated protein synthesis regulation via rapamycin-dependent mechanism (Wu et al. 2004). Internal ribosomal initiation of mRNA translation, as a step affects rapamycin and p70S6K, which is critical for survival of cells under transient apoptotic stress (Holcik et al. 2000). However, it has been proposed that preservation of protein synthesis via p70S6K may be one of the mechanisms through which insulin prevents apoptosis (Wu et al. 2004). Sirutin 1 (SIRT1)
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with a critical role in neurodegeneration and memory function (Giese 2009). Two isomers, GSK-3a and GSK-3b are most prominently expressed in the synapses of brain cells with particular abundance in hippocampus, neocortex and cerebellum (Yao et al. 2002). GSK-3b, a pro-apoptotic protein, is a key downstream target of the PI3K/Akt survival signaling pathway (Eldar-Finkelman 2002). It has been demonstrated that GSK-3b activity is required for apoptotic neuronal cell death (Crowder and Freeman 2000). GSK-3b expression is upregulated in the brain (Yang et al. 2008) suggesting that PI3K/Akt-mediated inactivation of GSK-3b is partly responsible for the neuroprotection (Lim et al. 2011). Thus, insulin activates glycogen synthase by promoting its dephosphorylation through inhibitory phosphorylation of GSK-3b by Akt (Fort et al. 2010).
Sirutin 1 (SIRT1) is a member of a highly conserved gene family (sirtuins) encoding NAD?-dependent deacetylases, which are expressed at high levels during early embryogenesis (Sakamoto et al. 2004) and in the adult mammalian brain (Ramadori et al. 2008). SIRT1 was upregulated in ALS and AD/taupathies (Kim et al. 2007), providing evidence of SIRT1 protecting diseased neurons (VazquezManrique et al. 2013). The insulin-induced increase in neurite outgrowth observed is also dependent on SIRT1 activation (Liu et al. 2013b). SIRT1 negatively regulates mTOR signaling to affect the neurite outgrowth of neurons and cell survival (Guo et al. 2011), and through its upstream inhibitory complex (TSC1/2) in fibroblast cells (Ghosh et al. 2010). The overexpression of SIRT1 deacetylates IRS2 and upregulates the phosphorylation level of IRS2 and ERK1/2 in the striatum (Wu et al. 2011).
Mammalian target of rapamycin (mTOR)
Inducible nitric oxide synthase (iNOS)
Signaling by target of rapamycin (mTOR) has been shown to modulate lifespan (Garelick and Kennedy 2011). TOR is
All brain cells produce nitric oxide (NO) from NO synthase (NOS) (Murphy et al. 1993). During abnormal or excessive
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stimulation, NO participates in neurotoxicity through mechanisms associated with DNA damage leading to poly(ADP-ribose) synthetase activation (Zhang et al. 1994), lipid peroxidation (Radi et al. 1991), and mitochondrial dysfunction and eventually cell death in neurodegeneration (Bolanos and Almeida 2010). In neurons, NO is transiently produced by activation of neuronal NOS (nNOS) and its over-production is involved in the neurotoxicity (Schulz et al. 1995). Our previous result showed that insulin significantly inhibited the NO levels in the H2O2 induced toxicity in glial cells (Ramalingam and Kim 2009). Hence, resident glial cells in the brain express iNOS and produce high levels of NO in response to a wide variety of pro-inflammatory and degenerative stimuli (Moncada and Bolanos 2006; Saha and Pahan 2006). Similarly, insulin downregulated lipopolysaccharides (LPS)-induced expression of iNOS in alveolar macrophages and insulin inhibited cytokine-induced iNOS expression in primary rat hepatocytes (Martins et al. 2008; Harbrecht et al. 2012). These results suggest that insulin not only regulates the expression of iNOS in peripheral tissues but also regulates the expression of iNOS in CNS cells (Li et al. 2013). B cell lymphoma 2 (Bcl-2) The Bcl-2 family proteins have one or more Bcl-2 homology domains and play a crucial role in intracellular apoptotic signal transduction by regulating permeability of the mitochondrial membrane (Yuan and Yankner 2000). The activation of PI3K/Akt influences on several downstream targets which could result in attenuation of apoptosis among which plays a very important role is mediated by pro- and anti-apoptotic proteins of Bcl-2 family (Luo et al. 2003; Shacka and Roth 2005). Akt phosphorylates Bad, and blocks the Bad-induced primary neuronal death (Datta et al. 1997). The overexpression of Bcl-2 genes prevents neuronal cell death and delays caspase-3 activation in neuronal cell injury (Maruyama et al. 2001; Nicolas et al. 2007). On the other hand, Bcl-2 phosphorylation induced by JNK could phosphorylate Bcl-2 and thus the phosphorylation might inactivate anti-apoptotic functions of Bcl-2 (Belka and Budach 2002; Haldar et al. 1995). Results reported that insulin significantly diminished the increase of Bcl-2 phosphorylation at Ser87 (Hui et al. 2005). Hence, Bcl-xl is one of the members of the Bcl-2 family which plays a key role in the survival of neurons. Bcl-xl deficient neurons are more vulnerable to cell death, although treatment with insulin or insulin-like factors can inhibit their apoptosis (Shindler et al. 1998). It is shown that insulin treatment decreases the rate of apoptosis by elevating Bcl-2 and Bcl-xl levels and reducing Bax levels (Jafari Anarkooli et al. 2009).
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Cytochrome c, caspases and PARP Cellular or biochemical signaling pathways involve mitochondria in apoptosis by releasing cytochrome c to the cytoplasm (Chan 2004; Kluck et al. 1997). Once cytochrome c is released from mitochondria, it directly binds to Apaf-1 in a dATP dependent fashion and promotes a conformational change that allows caspase-9 to join the complex, which has been termed the ‘apoptosome’ (Li et al. 1997; Ramalingam and Kim 2012). Caspase-9, which is an initiator of the cytochrome c-dependent caspase cascade, activates caspase-3, followed by caspases-2, -6, -8 and -10 activation downstream (Slee et al. 1999). Caspase3 is a key step in the execution process of apoptosis, and the inhibition of its activation could block apoptotic cell death (Hui et al. 2005). Insulin could decrease the activation of caspase-3, which might take effect at the final step of the apoptotic cascade (Hui et al. 2005). Caspase-3 also activates caspase-activated Ndase and leads to DNA damage. In addition, the downstream caspases cleave many substrate proteins, including poly(ADP-ribose) polymerase (PARP) (Endres et al. 1997). Excessive activation of PARP causes depletion of nicotinamide adenine dinucleotide and ATP, which ultimately leads to cellular failure and cell death (Chan 2004; Ramalingam and Kim 2012). Thus, It is also shown that insulin prevents caspase-3 activation and DNA fragmentation through the activation of the PI3K/Akt pathway and its subsequent inhibition of GSK-3b (Duarte et al. 2005; Duarte et al. 2008). Brain-derived neurotrophic factor (BDNF) Brain-derived neurotrophic factor (BDNF) is an important neurotrophin in the brain that supports the cell survival, differentiation and plasticity (Zhu et al. 2004). mTOR activation and the resulting enhancement of protein synthesis are induced by BDNF stimulation (Qi et al. 2010; Inamura et al. 2005). Hence, dysfunction of BDNF has been found in association with several disorders, such as mood disorders (Duman 2002; Neves-Pereira et al. 2002). Thus, BDNF was able to suppress active FOXO3a-induced increase of pro-apoptotic bim through activation of both PI3K/Akt and ERK signaling pathways (Zhu et al. 2004). Glucose transporter 4 (GLUT4) GLUT4, the major glucose transporter isoform (Merry and McConell 2009), is responsible for insulin-stimulated glucose uptake (Shisheva 2008). Gene transcription in response to oxidative stress affects insulin signaling by altering the availability of GLUT4 expect a decrease in the glucose uptake which results in insulin resistance (Rains and Jain 2011). The insulin-mediated signaling pathway
Mechanisms of action of brain insulin
activates GLUT4 including PI3K, PKC, Akt/PKB and other effectors (Fort et al. 2010). In the presence of insulin, oxytocinase (OX) and GLUT4 are expressed in the plasma membrane, where GLUT4 induces glucose uptake (Ramrez et al. 2012). It was suggested that the inhibition of the OX, following binding of angiotensin IV (Ang IV), could increase glucose uptake in neurons leading to an improvement of cognitive processes (Gard 2008; Stragier et al. 2008). Ras-related C3 botulinum toxin substrate 1 (Rac1) Rac1 (Rho family, small GTP binding protein) is a pleiotropic regulator of many cellular processes, including the cell cycle. Cell–cell adhesion also has been implicated as a PI3K downstream effector to control neurite outgrowth (Kita et al. 1998) and to promote colonic epithelial cell migration caused by epidermal growth factor (Dise et al. 2008). Thus, insulin acting on IRs activates PI3K/Akt/ mTOR signaling pathway, which in turn promotes Rac1dependent actin cytoskeletal rearrangement and dendritic spine formation (Lee et al. 2011). Nuclear factor-jB (NF-jB) The transcription factor nuclear factor-jB (NF-jB) has been proposed to form a critical bridge between oxidant stress and the cellular response (Barnes and Karin 1997; Baeuerle and Henkel 1994). NF-jB rapidly transports information to the nucleus, thereby ensures a quick and finely tuned cellular response (Schiekofer et al. 2006). The treatment of astrocytes with insulin before lipopolysaccharides (LPS) stimulation, significantly reduced the nuclear translocation of this transcription factor possibly by blocking inhibitor jBa (IjBa) degradation, as the level of p-IjBa was decreased when compared with the LPS-treated group (Li et al. 2013). However, administration of insulin before LPS suppressed the expression of iNOS by preventing the nuclear translocation of NF-jB in alveolar macrophages (Martins et al. 2008). In addition, treatment with insulin had no effect on LPS-induced PKB phosphorylation (Li et al. 2013). Alpha-synuclein (a-Syn) Alpha-synuclein (a-Syn) is a member of the synuclein family of proteins, which also includes b- and c-synuclein. All members of the family are predominantly neuronal proteins that under physiological conditions localize preferentially to presynaptic terminals (George 2002). a-Syn is a natively unfolded cytosolic protein and poorly defined cellular roles known for its association with Parkinson’s disease, dementia with Lewy bodies, and multiple atrophy
(Dickson et al. 1999; Spillantini and Goedert 2000). The presence of Lewy bodies within cells has been taken as the pathological feature of toxic a-Syn to initiate apoptosis pathways intracellularly (Waxman and Giasson 2009). a-Syn may be released upon cell death (El-Agnaf et al. 1998) or secreted from neuronal cells (El-Agnaf et al. 2003; Lee et al. 2005; Sung et al. 2005). a-Syn, potentially in the form of small oligomers, appears to induce mitochondrial fragmentation, which may be responsible for subsequent mitochondrial dysfunction and death (Kamp et al. 2010; Nakamura et al. 2011). a-Syn mutations can cause autosomal dominant PD, and a-Syn which is the main component of the pathological feature of PD: the Lewy body (Aviles-Olmos et al. 2013). a-Syn affects various mitochondrial pathways (Poon et al. 2005), especially the complex I inhibition, induce ROS production, oxidative stress and resultant neuronal death. Oxidants and antioxidants Oxidation reactions are essential for the liberation of free energy and ATP formation. Hence, uncontrolled oxidation reactions may be detrimental to cells via formation of reactive oxygen and nitrogen free radicals and may take part in the pathogenesis of many human ailments (Herrera et al. 2009). Emerging evidence shows that reactive oxygen and nitrogen species (RONS) also function as an insulinsignaling molecule in normal physiology and casts doubt on the potential beneficial effect of antioxidants (Chang and Chuang 2010). Thus, increased mitochondrial RONS generation of excessive metabolic flux induces insulin resistance (Chang and Chuang 2010) and lipid and protein oxidation end products, mostly malondialdehyde (MDA) and protein carbonyl (PCO) adducts (Dasgupta et al. 2013). From our study, insulin pretreatment inhibited the increase in the intracellular ROS levels and MDA levels in H2O2 induced oxidative stress in glial cells (Ramalingam and Kim 2009). Glucose stimulates superoxide dismutase (SOD) production through NADPH oxidase, a major source of superoxide, in neuronal tissues (Suh et al. 2007). Reduced glutathione (GSH) as a non-protein thiol source in the cell prevents lipid peroxidation (Niki et al. 1985). Insulin-stimulated hepatic GSH synthesis (Lu et al. 1990) has been found to correlate with the activity of glutathione peroxidase (GPx) (Oliveras-Lopez et al. 2008). GSH is known to play a very important role in neuroproduction (Bolanos et al. 1996). GSH synthesized in the cytosol can be translocated to other organelles, like mitochondria, defense against nitrosative stress-mediated damage to DNA, lipids and proteins (Heales and Bolanos 2002). In neurons, GSH is readily oxidized by nitrosative stress, and thus has been shown that cultured neurons rapidly die upon incubation in the presence of RONS (Bolanos et al. 1996).
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Conclusions Insulin signaling is a highly conserved pathway and normal intracellular signaling is involved in several aspects of brain physiology and alterations in this pathway have been implicated in the etiology of neurodegenerative diseases such as aging, AD, PD, HD and ALS. Aging is associated with reduction in the levels of insulin, insulin receptors and insulin receptor substrates. At present, there is a dearth of effective therapeutics for neurodegenerative diseases. Insulin can be synthesized de novo in the brain and highly enriched in the brain cortex, olfactory bulb, hippocampus, hypothalamus and amygdala. Therefore, utilizing insulin for therapeutic treatment in neurodegenerative situations could be attempted to reduce neuronal apoptosis well described. Thus, it seems likely that insulin metabolism could prove to have a significant role in modulating cerebral function following various forms of insults. With this, insulin might play a neuroprotective role against neurodegenerative diseases. Acknowledgments This work was supported by a post-doctoral fellowship grant from Kyung Hee University in 2011–2012 (KHU20110696). Conflict of interest The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of the paper.
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NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Mechanisms of action of brain insulin against neurodegenerative diseases Mahesh Ramalingam • Sung-Jin Kim
Received: 26 June 2013 / Accepted: 17 December 2013 Ó Springer-Verlag Wien 2014
Abstract Insulin, a pancreatic hormone, is best known for its peripheral effects on the metabolism of glucose, fats and proteins. There is a growing body of evidence linking insulin action in the brain to neurodegenerative diseases. Insulin present in central nervous system is a regulator of central glucose metabolism nevertheless this glucoregulation is not the main function of insulin in the brain. Brain is known to be specifically vulnerable to oxidative products relative to other organs and altered brain insulin signaling may cause or promote neurodegenerative diseases which invalidates and reduces the quality of life. Insulin located within the brain is mostly of pancreatic origin or is produced in the brain itself crosses the blood-brain barrier and enters the brain via a receptor-mediated active transport system. Brain Insulin, insulin receptor and insulin receptor substrate-mediated signaling pathways play important roles in the regulation of peripheral metabolism, feeding behavior, memory and maintenance of neural functions such as neuronal growth and differentiation, neuromodulation and neuroprotection. In the present review, we would like to summarize the novel biological and pathophysiological roles of neuronal insulin in neurodegenerative diseases and describe the main signaling pathways in use for therapeutic strategies in the use of insulin to the cerebral tissues and their biological applications to neurodegenerative diseases.
M. Ramalingam S.-J. Kim (&) Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University, 26, Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea e-mail: [email protected]
Keywords Insulin Neurodegenerative disease Brain Neuroprotection Brain signaling pathways
Introduction The brain consumes large amounts of oxygen to generate the adenosine triphosphate (ATP) and phosphocreatine required for the maintenance of cellular functional homeostasis (Halliwell 2006). However, part of the oxygen is physiologically diverted to the generation of reactive oxygen species (ROS) (Floyd and Hensley 2002). Hence, most of the oxygen-derived reactive species are unstable, short-lived and react extremely quickly with other molecules (Ramalingam and Kim 2012). These excessive ROS in normal cells can initiate tissue damage to the destruction of cellular components, including lipids, proteins and DNA which can induce generation of secondary reactive species and ultimately lead to cell death in neurodegenerative diseases (NDDs) via apoptosis and necrosis (Ramalingam and Kim 2012). Incidences of NDDs are projected to increase considerably as a result of the growing aging population in the coming decades (Pangalos et al. 2007). However, a major challenge in neurodegenerative disease research is to identify disease-modifying strategies (Vazquez-Manrique et al. 2013). Each of the NDDs has its distinct ecological processes and differently affects brain regions, mitochondrial changes, though in varying degrees, suggesting the connection of disease pathology to the overall character of neurodegeneration (Ramalingam and Kim 2012; Du and Yan 2010). Hence, the study of NDDs including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS) is expected to shed light on the mechanisms that
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underlie neurodegeneration (Vazquez-Manrique et al. 2013). Increasing evidence suggests that insulin and insulin signaling mechanisms are critical for neuronal survival in the NDDs (Hoyer and Lannert 2007). Normal intracellular insulin signaling is putatively involved in several aspects of brain physiology (Plum et al. 2005), and alterations in this pathway have been consistently implicated in the etiology of NDDs (Hoyer and Lannert 2007). Therefore, biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. In this review, we focused on identifying the relationship of the insulin network to the brain as well as to determine the mechanisms through which insulin dysregulation promotes NDDs (Craft et al. 2013).
Insulin Insulin is a peptide hormone of 5.8 kDa molecular weight secreted from beta cells of the endocrine pancreas (Reaven 1997). It is composed of two peptide chains connected to each other by disulfide linkages (Steiner and Oyer 1967). Insulin was first identified in the early 1920s as the major hypoglycemic hormone, capable of restoring normal blood glucose levels by its effects on glucose metabolism in the liver, skeletal muscle and adipose tissue (Konrad et al. 2005). Thus, the physiological functions of insulin are shown in Fig. 1. Nevertheless, freshly secreted pancreatic insulin exerts direct hormonal effects on the liver, while the remainder enters the larger systemic plasma volume (Jones and Shojaee-Moradie 2002). Insulin secretion is subject to control by nutrients, hormonal, neural and pharmacological factors. Among these, glucose is by far the most important regulator of the machinery of insulin secretion (Gembal et al. 1992). Diabetes is a group of metabolic diseases characterized by deficits in insulin production (Type 1) or impairment of insulin sensitivity (Type 2) (Stranahan and Mattson 2010). Insulin resistance, a syndrome characterized by a diminished ability of insulin to perform its normal
Fig. 1 Physiological functions of insulin. Right-pointing arrows denote stimulation, and round-tip arrows inhibition
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physiological functions, is the main feature of type 2 diabetes and the key factor in the development of the metabolic syndrome (Medina-Gomez et al. 2005). The development of insulin resistance is closely correlated with immune cell infiltration and inflammation, with clear links between the development of obesity, type 2 diabetes mellitus and cardiovascular disease (Hotamisligil 2006). However, the more widespread development of insulin resistance has also been proposed to be mediated through mitochondrial dysfunction (Stark and Roden 2007). Insulin release is regulated in response to the levels of blood glucose or other nutrients and thus insulin stimulates anabolic pathways through the regulation of carbohydrate, lipid and protein metabolism while it inhibits catabolism of these fuel reserves (Lara-Castro and Garvey 2004). Approximately 50 % of the insulin reaching the liver is degraded without passing on to the general, systemic circulation to the other tissues of the body (Chap et al. 1987). In normal subjects, insulin is secreted briskly in response to a meal (Jones and Shojaee-Moradie 2002).
Insulin on macromolecule metabolism Circulating insulin levels during fasting are 5–20 % of those measured after a meal required to maintain the balance with counter-regulatory hormones to prevent ketoacidosis (Konrad et al. 2005). In carbohydrate metabolism, insulin stimulates rapid glucose uptake, storage, and utilization of glucose by almost all tissues of the body particularly the muscle, liver and adipose tissues (Oh 2013). Insulin activates the glucose storage as glycogen synthesis and decreases liver phosphorylase activity, but increases the activity of glucokinase (Lawrence and Roach 1997). Insulin also increases glycolysis and pentose pathways to increase glucose utilization but decreases gluconeogenesis by deactivating gluconeogenic enzymes (Hales 1971). Insulin also regulates lipid metabolism (Oh 2013). It is a key regulator of the interplay between glucose and fatty acid metabolism (Konrad et al. 2005). Insulin stimulates glucose uptake into adipose tissue cells which when converted to glycerol and/or fatty acids is used as substrate in the synthesis of triglyceride, a storage form of fat (Williamson 1989). Insulin decreases the breakdown and mobilization of fatty acids from triglycerides by inhibiting the activity of hormone-sensitive lipase whereas by activating lipoprotein lipase in the wall of capillary vessels near adipocytes, it increases fatty acid translocation into adipocytes and storage in the form of triglycerides (Williamson 1989). It has long been appreciated that insulin affects protein metabolism and growth (Oh 2013). A cellular protein breakdown is a tightly controlled and highly specific
Mechanisms of action of brain insulin
process including the lysosomal pathway, the calciumdependent protease pathway or the ubiquitin–proteasome path (Goldberg and St John 1976). Insulin stimulates protein synthesis and storage through increasing amino acid uptake, transcription and mRNA translation, whereas insulin inhibits breakdown of proteins by inhibiting proteolysis, gluconeogenesis and lysosome activity (Miers and Barrett 1998).
(de Moura et al. 2010). Herewith, insulin and insulin receptor (IR)-mediated signaling pathways (together with the inseparable insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R)) seem to play a crucial role in the regulation of central nervous system (CNS) metabolism, neuronal growth and differentiation, neuromodulation and neuroprotection (Duarte et al. 2012).
Insulin receptors (IRs) Insulin and the brain Insulin is widely known as a peripheral regulator of glucose transport and molecular metabolism in the adipocyte, muscle and liver cells (Schulingkamp et al. 2000; Oh 2013), which involve a complex crosstalk between peripheral nutritional and other hormonal signals (Duarte et al. 2013). However, it has earlier been considered that the brain was insulin-independent over a long time (Oh 2013), but it is now known that little or no insulin is produced in the brain itself (particularly in pyramidal neurons, e.g., from hippocampus, prefrontal cortex, entorhinal cortex, and olfactory bulb, but not in glial cells) (Hoyer 2003), being then released by exocytosis (Clarke et al. 1986). Insulin crosses the blood–brain barrier (BBB) and enters the brain via a receptor-mediated active transport system (Baura et al. 1993) and thus may also be synthesized by neurons in the brain (Devaskar et al. 1994). Interestingly, it plays a very important role in the regulation of peripheral and central glucose metabolism, feeding behavior, neurotransmission, learning and memory, maintenance of neural functions, and is neuroprotective (Plum et al. 2005; Zhao and Alkon 2001; Gerozissis 2008). This is consistent with reports that insulin is highly enriched in the brain cortex, olfactory bulb, hippocampus, hypothalamus, and amygdala (Havrankova et al. 1978). The findings strongly suggest that brain insulin signaling is required for a normal mitochondrial function and metabolism (Cheng et al. 2009) that could be helpful to maintain the central regulation of energy balance in the brain and to avoid the development of neurodegenerative diseases associated with impaired learning, memory and age-related diseases (Correia et al. 2011; Talbot et al. 2012; Muller et al. 2013). Moreover, poorly controlled diabetes has deleterious consequences on multiple organ systems, including the brain (Stranahan and Mattson 2010). A rapid increase or decrease in glucose level potentiates ROS toxicity as well as contributes to neural injury (Dasgupta et al. 2013). Neuronal cells in the brain are highly sensitive to oxidative stress due to their large dependence on oxidative phosphorylation for energy as compared to other cells (Dasgupta et al. 2013). This creates a potential oxidative stressful condition in the brain even in normal situations
Insulin actions are mediated through the insulin receptor (IR). The IR is a membrane protein of tyrosine kinase receptor family comprised of two alpha and two beta subunits that is widely expressed in the brain (Lee et al. 2011; Nemoto et al. 2010) with relatively high density located in the olfactory bulbs, hypothalamus and hippocampus (Havrankova et al. 1978; Unger et al. 1989). It has been linked to a wide variety of physiological functions including the energy homeostasis, food intake and body weight, fertility and reproduction, learning and memory, as well as aging (Lee et al. 2011). Brain IRs are present in particularly high concentrations in neurons, and at much lower levels in glial cells (Schwartz et al. 1992; Unger et al. 1989) and the neuronal IR signal transduction is similar to that of peripheral IRs (Salkovic-Petrisic et al. 2006).
Insulin-like growth factor-1 (IGF-1) Insulin-like growth factor-1 (IGF-1) is a basic polypeptide that is widely expressed in the CNS (Joseph D’Ercole and Ye 2008). IGF-1 belongs to the insulin-like growth factor (IGF) family of proteins, to which the agonists IGF1 and IGF2, the receptors IGF1R and IGF2R, and several IGFbinding proteins (IGFBP1-7) belong (Fernandez and Torres-Aleman 2012; Duan 2002; Bondy and Cheng 2004). Both IGF1 and IGF2 signal through the IGF1R leading to the growth and metabolic effects via the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway (Suh et al. 2013). IGF-1 is a crucial factor involved in normal cognitive function and successful aging (Denley et al. 2005; Carson et al. 1993; Camacho-Hubner et al. 2002). Impaired hippocampal insulin/IGF-1 action could result in cognition deficit and subsequent neuronal apoptosis (Li et al. 2002). It also provides effective protection against loss of dopaminergic neurons (Guan et al. 2000; Quesada et al. 2008; Offen et al. 2001). Increased serum IGF-1 levels in early PD may reflect a compensatory effort to protect dopaminergic neurons from degeneration and/or may be as a result of an increased dopamine turnover as compensation for already diminished dopaminergic function (Picillo et al. 2013).
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Insulin receptor substrates (IRSs) Insulin receptor substrates (IRS) are signaling adaptor proteins that function as intermediates of activated cell surface receptors, most notably for the IR and IGF-1R (Metz and Houghton 2011). Binding of insulin to the IR and IGF-1R activates the tyrosine kinase domain on the IR and IGF-1R, which results in tyrosine phosphorylation of multiple insulin receptor substrates (IRSs) (Holscher et al. 2008; Nemoto et al. 2010; Takeda et al. 2011). Phosphorylated IRS proteins activate several downstream signaling pathways, including PI3K/Akt/GSK-3 and Ras/MEK/ERK (Nemoto et al. 2010). Thus, the Ras/MEK/ERK pathway activates the downstream target cAMP response element binding protein (CREB), which is involved in long-term memory formation in the brain (Tully et al. 2003; Liu et al. 2013a).
Cerebral insulin resistance Insulin resistance is a common pathological state in which target cells failed to respond to ordinary levels of circulating insulin (Kahn and Flier 2000). It is generally agreed that insulin located within the brain is mostly of pancreatic origin, having passed through the BBB. Although there is little debate about the amount of insulin that is produced de novo within the CNS (Umegaki 2013). Insulin can reach high levels in the brain (Schechter et al. 1992; LeRoith 1983) and exert long-term neuronal trophic effects (Schulingkamp et al. 2000). Insulin resistance occurs when the cells (insulin receptors) are progressively unable to have a proper insulin response resulting in an inadequate entry of glucose in the cells (Tremblay-Mercier 2012). Insulin resistance is either a precursor or key component of numerous modern major health problems of industrialized societies, including obesity, metabolic syndrome, cardiovascular disorders, nonalcoholic fatty liver disease, depression, Alzheimer’s disease, asthma, some cancers and aging (Ning et al. 2011). Acute elevations of plasma insulin levels have been found to correlate with cerebro-spinal fluid (CSF) insulin concentrations in healthy, normal weight humans (Yanagita et al. 2013). Cerebral insulin resistance is seen as the result of various mechanisms at different levels (Yanagita et al. 2013). In addition, the role of insulin signaling in the development of insulin resistance is more due to the direct effects of insulin on insulin-signaling components, including the IR itself (Shanik et al. 2008). Nevertheless, fats may be unable to induce insulin resistance without insulin (Ning et al. 2011). Thus, insulin signaling itself is a legitimate target for prevention and reversion of insulin resistance and its numerous associated major health problems (Ning et al. 2011).
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AD patients have an increased risk of hyperinsulinemia and hyperglycemia relative to healthy controls (Meneilly et al. 1993; Razay and Wilcock 1994). Restoration of insulin signaling by the proinsulin C-peptide prevents deleterious effects of type-1 diabetes in rats (Sima and Li 2005), while a comparison of type-2 diabetes versus type-1 diabetes in rats showed that neuronal loss, neurite degeneration, impaired amyloid precursor protein (APP) metabolism, increased hyperphosphorylated tau protein (P-Tau) and dysfunctional insulin/IGF-1 signaling were more severe in type-2 diabetes, probably as a result of insulin resistance (Li et al. 2007).
Insulin and neurodegenerative diseases Insulin acts as a neuropeptide in the brain to regulate food intake, body weight, mood, cognitive function, memory, neuronal survival and synaptic plasticity (Laron 2009; Stockhorst et al. 2004). To this extent, an increased understanding of the complexity of insulin signaling in the brain and the interactions between central and peripheral effects of insulin is desirable (Gerozissis 2008). Conversely, dysregulated insulin receptor signaling (e.g. insulin deficiency and insulin resistance) in the brain is involved in the neurodegenerative diseases (Yanagita et al. 2013). Therefore, altered or defective insulin action in the brain may cause or promote metabolic diseases such as obesity, diabetes or AD suggesting that central insulin resistance might not only be a consequence but also a starting point for the development of obesity and possibly of type-2 diabetes (Gerozissis 2008). Alzheimer’s disease (AD) AD is a neurodegenerative disorder that typically occurs late in life and is characterized by memory loss and cognitive impairment (Pandini et al. 2013) associated with progressive neuronal degeneration and the accumulation of neurofibrillary tangles and insoluble b-amyloid (Ab) plaques in the CNS (Pandini et al. 2013). Insulin performs important functions in brain regions involved in learning and memory (Zhao and Alkon 2001; Craft and Watson 2004). In addition to its typical metabolic effects, insulin also activates mechanisms relating to neuronal activity, including APP processing, Ab generation, and Tau protein phosphorylation as well as all major components of AD pathogenesis (Pandini et al. 2013). AD patients also have a reduced cerebro-spinal fluid to plasma insulin ratio (Craft et al. 1998). Hence, insulin signaling impairment leads to abnormal APP processing and Ab accumulation (Pandini et al. 2013). These studies suggest a possible role of impaired insulin action (i.e. insulin resistance and/or insulin deficiency) in the pathogenesis of AD (Pandini et al. 2013).
Mechanisms of action of brain insulin
Moreover, insulin resistance leads to accelerated lipolysis and increased free fatty acid levels, leading to higher and more prolonged post-prandial excursions of very low-density lipoprotein (VLDL) and other deleterious lipids (Craft et al. 2013). This tendency precedes Ab deposition in the brain (Burgess et al. 2006), and high fat feeding increases brain amyloid burden (Sechi 1999). Interestingly, intranasal insulin administration has an improving effect of learning and memory as well as a mood stabilizing effect in the patients with AD and healthy volunteers (Reger et al. 2006; Reger et al. 2008; Benedict et al. 2004; Benedict et al. 2007). Thus, insulin receptor signaling attracts attention as the molecular target for the treatment of cognitive and mood disorders (Yanagita et al. 2013). Parkinson’s disease (PD) PD is clinically characterized by cardinal motor symptoms including bradykinesia, rigidity, rest tremor and postural instability caused by the progressive loss of dopaminergic neurons in the substantia nigra (Braak et al. 2003). PD and type-2 diabetes mellitus may relate to abnormalities in a common pathway or indirectly as a consequence of chronic hyperglycemia or hyperinsulinemia (Aviles-Olmos et al. 2013). Neuropathological studies of patients with PD have shown that insulin receptors are densely represented on the dopaminergic neurons of the substantia nigra pars compacta (Unger et al. 1991) and loss of insulin receptor immunoreactivity and messenger RNA in the substantia nigra pars compacta of patients with PD coincides with loss of tyrosine hydroxylase messenger RNA (the rate-limiting enzyme in dopamine synthesis (Moroo et al. 1994; Takahashi et al. 1996). IGF-1 has been shown to provide effective protection against loss of dopaminergic neurons (Guan et al. 2000; Quesada et al. 2008; Offen et al. 2001). IGF-1 was found to relate to dopaminergic score (Picillo et al. 2013). Huntington’s disease (HD) HD is an autosomal dominantly inherited progressive neurodegenerative disorder that manifested in cognitive, psychiatric and motor symptoms (Zadori et al. 2011). Normoglycemic HD patients have been shown to have impaired insulin sensitivity and secretion (Lalic et al. 2008). HD patient examined had the smallest beta-cell area and lowest level of insulin mRNA (Bacos et al. 2008). Hence, reduced insulin signaling through reduced levels of IRS-2 or IGF-1 improves disease phenotypes in mouse models of HD (Sadagurski et al. 2011). Moreover, Rhes has also been shown to participate in Akt signaling through other mechanisms. Therefore, it not only interacts with Akt directly to enhance its phosphorylation by growth factors (Bang et al. 2012), but also allows for its
dephosphorylation with alternate cues (Harrison and Lahoste 2013). PI3K-Akt-mTOR signaling has a role in increasing neuronal size and dendritic complexity (Kumar et al. 2005).
Insulin on signaling pathways Under physiological condition, several ‘intrinsic’ downstream serine/threonine kinases in the insulin pathway such as Akt/PKB, mTOR, and ERK1 phosphorylate serine/ theronine residues of the IRS proteins and inhibit insulin signaling as a negative feedback regulation (De Hert et al. 2012). In neurons, the PI3K [ Akt [ GSK3beta [ BAD, FOXO, TOR and GLUTs pathways are clearly critical for survival signaling (Cole and Frautschy 2007). Thus, all of these pathways contribute to the hypothesis that increased insulin signaling in the brain would promote neuronal development and continued survival in vitro and in vivo (Cole and Frautschy 2007). Therefore, the proposed consequences of normal and impaired insulin signaling networks are diagrammatically represented in Figs. 2 and 3. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt/PKB) PI3K is a key anti-apoptotic effector in the growth factor signaling pathway (Hui et al. 2005). Akt/PKB, a 57-kDa protein-serine/threonine kinase expressed as Akt1 and Akt2 (Downward 1998), serves a key role in mediating the antiapoptotic actions of growth factors on cell (Datta et al. 1997) and plays an important role in neuronal protection (Hui et al. 2005). Stimulation of tyrosine kinase growth factor receptors activates PI3K, leading to Akt activation (Hui et al. 2005), further downstream, vesicular translocation of glucose transporter 4 (GLUT4) and activation of glucose transport (Le Marchand-Brustel et al. 1999). Previous studies clearly showed that insulin could effectively activate Akt in brain cells (Kim and Han 2005; Ramalingam and Kim 2009). Akt activation is correlated with phosphorylation of Thr-308 at its catalytic domain and of Ser-473 at the C terminus (Hui et al. 2005) and inactivates glycogen synthase kinase-3 (GSK-3b), Bad, and the forkhead transcription factors (Fort et al. 2010). Thus, much of insulin’s downstream signaling to affect metabolic events involves the activation of PI3K (Piwkowska et al. 2012). However, IGF-1 binding IGF-1R prevents neuronal death after transient forebrain ischemia in rats (Hui et al. 2005). Mitogen-activated protein kinases (MAPKs) The mitogen-activated protein kinases (MAPKs) are also sensitive to oxidative stress conditions, which entails an
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M. Ramalingam, S.-J. Kim Fig. 2 Diagrammatic representation of brain insulin signaling pathways. Rightpointing arrows denote stimulation, and round-tip arrows inhibition
Fig. 3 Diagrammatic representation of impaired brain insulin signaling pathways. Right-pointing arrows denote stimulation, and round-tip arrows inhibition
enhanced generation of hydrogen peroxide (H2O2) or peroxynitrite, resulting in their activation (Yin et al. 2012). c-Jun N-terminal kinase (JNK), a member of the MAPK family, is important in inducing neuronal death (Hui et al. 2005). The JNKs are encoded by three genes: JNK1, JNK2 and JNK3 (Hui et al. 2005). Activated JNK, in turn, phosphorylates a number of transcription factors, especially the c-Jun of the components of activator protein-1 (AP-1), and cellular proteins, particularly those associated with apoptosis (Manning and Davis 2003). In addition, JNK also plays a central role in the progression of insulin resistance; a likely mechanism that entails the phosphorylation of the IRS-1 at Ser307, leading to inhibition of the insulin-
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promoted tyrosine phosphorylation of IRS (Aguirre et al. 2000). Similarly, activated JNK specifically phosphorylates the N-terminal activation domain of the transcription factor c-Jun at serine 63 and 73 thereby increasing transcriptional activity of c-Jun (Minden et al. 1994). Brain ischemia promotes both the expression and phosphorylation on serine 63 of c-Jun (Guan et al. 2005). Therefore, the decrease in intracellular Ab stimulated by insulin in N2a murine neuroblastoma cells occurs via the MAPK pathway activation (Gasparini et al. 2001). Thus, the neuroprotective action of insulin is possibly by activating anti-apoptotic signaling of PI3K/Akt pathway and blocking the activation of JNK signaling (Kim and Han 2005; Hui et al. 2005).
Mechanisms of action of brain insulin
Forkhead box ‘Other’ (FOXO) proteins Forkhead box ‘Other’ (FOXO) proteins have emerged as an important targets of insulin and growth factor action (Barthel et al. 2005). Hence, they are able to integrate several types of external stimuli to regulate gene expression and modulate cell cycle arrest, apoptosis, autophagy, angiogenesis, differentiation, stress resistance, stem cell maintenance, glucogenesis and food intake (VazquezManrique et al. 2013). Insulin and IGF-1 both inhibit FOXOs by a mechanism that requires PI3K (Anton et al. 2007; Nakae et al. 1999; Rena et al. 1999), and 3-phosphoinositide-dependent protein kinase-1 (PDK1) (Rena et al. 2002). FOXO3a (forkhead box, class O, 3a) belongs to the family of mammalian FOXOs with a ubiquitous distribution and high expression in the brain (Furuyama et al. 2000), which are regulated by growth factor receptorinduced activation of the PI3K/Akt signaling pathway (Zhu et al. 2004). Activation of growth receptors, such as insulin, IGF-1 and nerve growth factor (NGF), activates PI3K and subsequently increases the production of PI3,4biphosphate and PI3,4,5-triphosphate, leading to phosphorylation and activation of Akt (Burgering and Coffer 1995). Therefore, activation of Akt by insulin/IGF-1 causes phosphorylation of FOXO1a on Thr24, Ser256 and Ser319 (Nakae et al. 1999; Rena et al. 1999) as well as FOXO3a at the threonine32, serine253 and serine315 sites (Brunet et al. 1999). Glycogen synthase kinase-3 (GSK-3)
a member of the phosphoinositol kinase-related kinase (PIKK) family of kinases and phosphorylates proteins on serine and threonine residues (Garelick and Kennedy 2011). Enhanced mTORC1 (functionally distinct complex of mTOR) function is mediated through activation of receptors for growth factors, hormones and cytokines (Garelick and Kennedy 2011). Moreover, binding of insulin to the IR recruits IRS and activates the catalytic subunit of PI3K, as well as generates the production of phosphatidylinositol (3,4,5)-triphosphate (PIP3). Thus, PI3K recruits 3-phosphoinositide-dependent kinase 1 (PDK1) to phosphorylate Akt which promotes cell growth and survival through its numerous targets (Scheid and Woodgett 2001). p70S6K The 70 kDa ribosomal protein S6 kinase, p70S6K, is one of the downstream effectors of the PI3K/Akt/mTOR pathway which plays a key role in insulin-stimulated protein synthesis regulation via rapamycin-dependent mechanism (Wu et al. 2004). Internal ribosomal initiation of mRNA translation, as a step affects rapamycin and p70S6K, which is critical for survival of cells under transient apoptotic stress (Holcik et al. 2000). However, it has been proposed that preservation of protein synthesis via p70S6K may be one of the mechanisms through which insulin prevents apoptosis (Wu et al. 2004). Sirutin 1 (SIRT1)
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with a critical role in neurodegeneration and memory function (Giese 2009). Two isomers, GSK-3a and GSK-3b are most prominently expressed in the synapses of brain cells with particular abundance in hippocampus, neocortex and cerebellum (Yao et al. 2002). GSK-3b, a pro-apoptotic protein, is a key downstream target of the PI3K/Akt survival signaling pathway (Eldar-Finkelman 2002). It has been demonstrated that GSK-3b activity is required for apoptotic neuronal cell death (Crowder and Freeman 2000). GSK-3b expression is upregulated in the brain (Yang et al. 2008) suggesting that PI3K/Akt-mediated inactivation of GSK-3b is partly responsible for the neuroprotection (Lim et al. 2011). Thus, insulin activates glycogen synthase by promoting its dephosphorylation through inhibitory phosphorylation of GSK-3b by Akt (Fort et al. 2010).
Sirutin 1 (SIRT1) is a member of a highly conserved gene family (sirtuins) encoding NAD?-dependent deacetylases, which are expressed at high levels during early embryogenesis (Sakamoto et al. 2004) and in the adult mammalian brain (Ramadori et al. 2008). SIRT1 was upregulated in ALS and AD/taupathies (Kim et al. 2007), providing evidence of SIRT1 protecting diseased neurons (VazquezManrique et al. 2013). The insulin-induced increase in neurite outgrowth observed is also dependent on SIRT1 activation (Liu et al. 2013b). SIRT1 negatively regulates mTOR signaling to affect the neurite outgrowth of neurons and cell survival (Guo et al. 2011), and through its upstream inhibitory complex (TSC1/2) in fibroblast cells (Ghosh et al. 2010). The overexpression of SIRT1 deacetylates IRS2 and upregulates the phosphorylation level of IRS2 and ERK1/2 in the striatum (Wu et al. 2011).
Mammalian target of rapamycin (mTOR)
Inducible nitric oxide synthase (iNOS)
Signaling by target of rapamycin (mTOR) has been shown to modulate lifespan (Garelick and Kennedy 2011). TOR is
All brain cells produce nitric oxide (NO) from NO synthase (NOS) (Murphy et al. 1993). During abnormal or excessive
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stimulation, NO participates in neurotoxicity through mechanisms associated with DNA damage leading to poly(ADP-ribose) synthetase activation (Zhang et al. 1994), lipid peroxidation (Radi et al. 1991), and mitochondrial dysfunction and eventually cell death in neurodegeneration (Bolanos and Almeida 2010). In neurons, NO is transiently produced by activation of neuronal NOS (nNOS) and its over-production is involved in the neurotoxicity (Schulz et al. 1995). Our previous result showed that insulin significantly inhibited the NO levels in the H2O2 induced toxicity in glial cells (Ramalingam and Kim 2009). Hence, resident glial cells in the brain express iNOS and produce high levels of NO in response to a wide variety of pro-inflammatory and degenerative stimuli (Moncada and Bolanos 2006; Saha and Pahan 2006). Similarly, insulin downregulated lipopolysaccharides (LPS)-induced expression of iNOS in alveolar macrophages and insulin inhibited cytokine-induced iNOS expression in primary rat hepatocytes (Martins et al. 2008; Harbrecht et al. 2012). These results suggest that insulin not only regulates the expression of iNOS in peripheral tissues but also regulates the expression of iNOS in CNS cells (Li et al. 2013). B cell lymphoma 2 (Bcl-2) The Bcl-2 family proteins have one or more Bcl-2 homology domains and play a crucial role in intracellular apoptotic signal transduction by regulating permeability of the mitochondrial membrane (Yuan and Yankner 2000). The activation of PI3K/Akt influences on several downstream targets which could result in attenuation of apoptosis among which plays a very important role is mediated by pro- and anti-apoptotic proteins of Bcl-2 family (Luo et al. 2003; Shacka and Roth 2005). Akt phosphorylates Bad, and blocks the Bad-induced primary neuronal death (Datta et al. 1997). The overexpression of Bcl-2 genes prevents neuronal cell death and delays caspase-3 activation in neuronal cell injury (Maruyama et al. 2001; Nicolas et al. 2007). On the other hand, Bcl-2 phosphorylation induced by JNK could phosphorylate Bcl-2 and thus the phosphorylation might inactivate anti-apoptotic functions of Bcl-2 (Belka and Budach 2002; Haldar et al. 1995). Results reported that insulin significantly diminished the increase of Bcl-2 phosphorylation at Ser87 (Hui et al. 2005). Hence, Bcl-xl is one of the members of the Bcl-2 family which plays a key role in the survival of neurons. Bcl-xl deficient neurons are more vulnerable to cell death, although treatment with insulin or insulin-like factors can inhibit their apoptosis (Shindler et al. 1998). It is shown that insulin treatment decreases the rate of apoptosis by elevating Bcl-2 and Bcl-xl levels and reducing Bax levels (Jafari Anarkooli et al. 2009).
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Cytochrome c, caspases and PARP Cellular or biochemical signaling pathways involve mitochondria in apoptosis by releasing cytochrome c to the cytoplasm (Chan 2004; Kluck et al. 1997). Once cytochrome c is released from mitochondria, it directly binds to Apaf-1 in a dATP dependent fashion and promotes a conformational change that allows caspase-9 to join the complex, which has been termed the ‘apoptosome’ (Li et al. 1997; Ramalingam and Kim 2012). Caspase-9, which is an initiator of the cytochrome c-dependent caspase cascade, activates caspase-3, followed by caspases-2, -6, -8 and -10 activation downstream (Slee et al. 1999). Caspase3 is a key step in the execution process of apoptosis, and the inhibition of its activation could block apoptotic cell death (Hui et al. 2005). Insulin could decrease the activation of caspase-3, which might take effect at the final step of the apoptotic cascade (Hui et al. 2005). Caspase-3 also activates caspase-activated Ndase and leads to DNA damage. In addition, the downstream caspases cleave many substrate proteins, including poly(ADP-ribose) polymerase (PARP) (Endres et al. 1997). Excessive activation of PARP causes depletion of nicotinamide adenine dinucleotide and ATP, which ultimately leads to cellular failure and cell death (Chan 2004; Ramalingam and Kim 2012). Thus, It is also shown that insulin prevents caspase-3 activation and DNA fragmentation through the activation of the PI3K/Akt pathway and its subsequent inhibition of GSK-3b (Duarte et al. 2005; Duarte et al. 2008). Brain-derived neurotrophic factor (BDNF) Brain-derived neurotrophic factor (BDNF) is an important neurotrophin in the brain that supports the cell survival, differentiation and plasticity (Zhu et al. 2004). mTOR activation and the resulting enhancement of protein synthesis are induced by BDNF stimulation (Qi et al. 2010; Inamura et al. 2005). Hence, dysfunction of BDNF has been found in association with several disorders, such as mood disorders (Duman 2002; Neves-Pereira et al. 2002). Thus, BDNF was able to suppress active FOXO3a-induced increase of pro-apoptotic bim through activation of both PI3K/Akt and ERK signaling pathways (Zhu et al. 2004). Glucose transporter 4 (GLUT4) GLUT4, the major glucose transporter isoform (Merry and McConell 2009), is responsible for insulin-stimulated glucose uptake (Shisheva 2008). Gene transcription in response to oxidative stress affects insulin signaling by altering the availability of GLUT4 expect a decrease in the glucose uptake which results in insulin resistance (Rains and Jain 2011). The insulin-mediated signaling pathway
Mechanisms of action of brain insulin
activates GLUT4 including PI3K, PKC, Akt/PKB and other effectors (Fort et al. 2010). In the presence of insulin, oxytocinase (OX) and GLUT4 are expressed in the plasma membrane, where GLUT4 induces glucose uptake (Ramrez et al. 2012). It was suggested that the inhibition of the OX, following binding of angiotensin IV (Ang IV), could increase glucose uptake in neurons leading to an improvement of cognitive processes (Gard 2008; Stragier et al. 2008). Ras-related C3 botulinum toxin substrate 1 (Rac1) Rac1 (Rho family, small GTP binding protein) is a pleiotropic regulator of many cellular processes, including the cell cycle. Cell–cell adhesion also has been implicated as a PI3K downstream effector to control neurite outgrowth (Kita et al. 1998) and to promote colonic epithelial cell migration caused by epidermal growth factor (Dise et al. 2008). Thus, insulin acting on IRs activates PI3K/Akt/ mTOR signaling pathway, which in turn promotes Rac1dependent actin cytoskeletal rearrangement and dendritic spine formation (Lee et al. 2011). Nuclear factor-jB (NF-jB) The transcription factor nuclear factor-jB (NF-jB) has been proposed to form a critical bridge between oxidant stress and the cellular response (Barnes and Karin 1997; Baeuerle and Henkel 1994). NF-jB rapidly transports information to the nucleus, thereby ensures a quick and finely tuned cellular response (Schiekofer et al. 2006). The treatment of astrocytes with insulin before lipopolysaccharides (LPS) stimulation, significantly reduced the nuclear translocation of this transcription factor possibly by blocking inhibitor jBa (IjBa) degradation, as the level of p-IjBa was decreased when compared with the LPS-treated group (Li et al. 2013). However, administration of insulin before LPS suppressed the expression of iNOS by preventing the nuclear translocation of NF-jB in alveolar macrophages (Martins et al. 2008). In addition, treatment with insulin had no effect on LPS-induced PKB phosphorylation (Li et al. 2013). Alpha-synuclein (a-Syn) Alpha-synuclein (a-Syn) is a member of the synuclein family of proteins, which also includes b- and c-synuclein. All members of the family are predominantly neuronal proteins that under physiological conditions localize preferentially to presynaptic terminals (George 2002). a-Syn is a natively unfolded cytosolic protein and poorly defined cellular roles known for its association with Parkinson’s disease, dementia with Lewy bodies, and multiple atrophy
(Dickson et al. 1999; Spillantini and Goedert 2000). The presence of Lewy bodies within cells has been taken as the pathological feature of toxic a-Syn to initiate apoptosis pathways intracellularly (Waxman and Giasson 2009). a-Syn may be released upon cell death (El-Agnaf et al. 1998) or secreted from neuronal cells (El-Agnaf et al. 2003; Lee et al. 2005; Sung et al. 2005). a-Syn, potentially in the form of small oligomers, appears to induce mitochondrial fragmentation, which may be responsible for subsequent mitochondrial dysfunction and death (Kamp et al. 2010; Nakamura et al. 2011). a-Syn mutations can cause autosomal dominant PD, and a-Syn which is the main component of the pathological feature of PD: the Lewy body (Aviles-Olmos et al. 2013). a-Syn affects various mitochondrial pathways (Poon et al. 2005), especially the complex I inhibition, induce ROS production, oxidative stress and resultant neuronal death. Oxidants and antioxidants Oxidation reactions are essential for the liberation of free energy and ATP formation. Hence, uncontrolled oxidation reactions may be detrimental to cells via formation of reactive oxygen and nitrogen free radicals and may take part in the pathogenesis of many human ailments (Herrera et al. 2009). Emerging evidence shows that reactive oxygen and nitrogen species (RONS) also function as an insulinsignaling molecule in normal physiology and casts doubt on the potential beneficial effect of antioxidants (Chang and Chuang 2010). Thus, increased mitochondrial RONS generation of excessive metabolic flux induces insulin resistance (Chang and Chuang 2010) and lipid and protein oxidation end products, mostly malondialdehyde (MDA) and protein carbonyl (PCO) adducts (Dasgupta et al. 2013). From our study, insulin pretreatment inhibited the increase in the intracellular ROS levels and MDA levels in H2O2 induced oxidative stress in glial cells (Ramalingam and Kim 2009). Glucose stimulates superoxide dismutase (SOD) production through NADPH oxidase, a major source of superoxide, in neuronal tissues (Suh et al. 2007). Reduced glutathione (GSH) as a non-protein thiol source in the cell prevents lipid peroxidation (Niki et al. 1985). Insulin-stimulated hepatic GSH synthesis (Lu et al. 1990) has been found to correlate with the activity of glutathione peroxidase (GPx) (Oliveras-Lopez et al. 2008). GSH is known to play a very important role in neuroproduction (Bolanos et al. 1996). GSH synthesized in the cytosol can be translocated to other organelles, like mitochondria, defense against nitrosative stress-mediated damage to DNA, lipids and proteins (Heales and Bolanos 2002). In neurons, GSH is readily oxidized by nitrosative stress, and thus has been shown that cultured neurons rapidly die upon incubation in the presence of RONS (Bolanos et al. 1996).
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Conclusions Insulin signaling is a highly conserved pathway and normal intracellular signaling is involved in several aspects of brain physiology and alterations in this pathway have been implicated in the etiology of neurodegenerative diseases such as aging, AD, PD, HD and ALS. Aging is associated with reduction in the levels of insulin, insulin receptors and insulin receptor substrates. At present, there is a dearth of effective therapeutics for neurodegenerative diseases. Insulin can be synthesized de novo in the brain and highly enriched in the brain cortex, olfactory bulb, hippocampus, hypothalamus and amygdala. Therefore, utilizing insulin for therapeutic treatment in neurodegenerative situations could be attempted to reduce neuronal apoptosis well described. Thus, it seems likely that insulin metabolism could prove to have a significant role in modulating cerebral function following various forms of insults. With this, insulin might play a neuroprotective role against neurodegenerative diseases. Acknowledgments This work was supported by a post-doctoral fellowship grant from Kyung Hee University in 2011–2012 (KHU20110696). Conflict of interest The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of the paper.
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