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AGEs/RAGE-related neurodegeneration: daf-16 as a mediator, insulin as an ameliorant and C. elegans as an expedient research model Adi Pinkas, and Michael Aschner Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.6b00264 • Publication Date (Web): 05 Oct 2016 Downloaded from http://pubs.acs.org on October 13, 2016

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Chemical Research in Toxicology

AGEs/RAGE-related neurodegeneration: daf-16 as a mediator, insulin as an ameliorant and C. elegans as an expedient research model.

Adi Pinkas and Michael Aschner*

Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Forchheimer Building, Room 209 Bronx, NY 10461 Tel: 718.430.2317 Email: [email protected]

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Abstract Advanced glycation end-products (AGEs) are non-enzymatically glycated proteins, lipids and nucleic acids. These compounds both originate exogenously and are formed endogenously, and are associated, along with one of their receptors – RAGE, with a variety of pathologies and neurodegeneration. Some of their deleterious effects include affecting insulin signaling and FOXO-related pathways in both receptordependent and -independent manner. A potential ameliorating agent for these effects is insulin, which is being studied in several in vivo and in vitro models; one of these models is C. elegans, whose maintenance, genetic malleability and well-described longevity-related pathways make it an optimal complementary model for assessing these objectives. In the realm of neuroscience, this model is currently being used only for general assessment of neurodegeneration and shortened lifespan; We suggest that characterization of a) the effects of AGEs/RAGE on specific neurotransmitter systems, b) the role of the daf-2/daf-16 pathway in these neurodegenerative processes and c) the amending properties of insulin would greatly contribute to a more comprehensive understanding of AGEs-related neurodegeneration and, potentially, would lead to developing efficient therapeutic strategies. Introduction AGEs and RAGE The non-enzymatic reaction between reducing sugars and proteins, lipids or nucleic acids (glycation) is a well-known and studied phenomenon, which leads to the formation of advanced glycation end products (AGEs).1-6 Initially, AGEs were studied as exogenous compounds that originated in certain foods due to the maillard reaction, which occurs in high temperature and low humidity cooking.3, 5, 7-12 More recently, the focus has shifted to endogenous AGEs, which are formed and accumulate under hyperglycemic conditions.13, 14 While AGEs per se are associated with inflammation and oxidative stress,15, 16 their receptor-mediated detrimental effects have also been described: of the different receptors to which


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AGEs bind, the one most studied with regards to pathology is the receptor for advanced glycation end products (RAGE).17-23 AGEs and RAGE have been associated with several neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), CreutzfeldtJakob’s disease (CJD), amyotrophic lateral sclerosis (ALS), familial amyloid polyneuropathy and peripheral neuropathies.24-29 Some of the therapeutic strategies aimed at prevention and/or treatment of AGEs/RAGE-related pathologies include the elimination of circulating AGEs and the prevention of RAGE-mediated signal transduction.27, 30, 31 The C. elegans model for AGEs-related pathologies under hyper-glycemic conditions Caenorhabditis elegans (C. elegans), a small translucent nematode, is an expedient model for a variety of human diseases and neurodegenerative disorders.32, 33 (reviews) Among other phenomena, this model has been used to study the detrimental effects of AGEs formation and accumulation under hyperglycemic conditions and also potential therapeutic strategies.34-37 Two characteristic that are being studied in C. elegans with regards to hyperglycemia and AGEs formation and accumulation, are lifespan and neuronal function. A reduction in lifespan is observed under high glucose conditions, along with structural damage in the nervous system and impaired motility.34, 38-40 This reduction has been explained to be secondary to elevated oxidative stress, leading to a reduction in the activity of glyoxalase-1 – an enzyme preventing AGEs formation and accumulation.34, 41 Subsequently, extension of lifespan under glucose restriction has been explained by increased antioxidant defenses.40 Longevity in C. elegans, along with metabolism and development, is controlled by the daf-2/daf-16 pathway: daf-16 is a gene encoding the orthologue of the mammalian FOXO transcription factors, which promotes stress response and cell survival.42 daf-2 is a gene encoding the insulin-like growth factor receptor 1 (IGF-1),43-45 and is serves as a negative regulator of daf-16, A decrease in daf-2 signaling leads to increased daf-16/FOXO activity and, consequently, an extended lifespan in C. elegans.44-46



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Insulin and neurodegeneration In addition to its role in lifespan regulation, insulin signaling in the central nervous system (CNS) is associated with neuroprotection, neurodegeneration, neuronal and glial growth, dendritic plasticity and synaptic activity.47-53 Not surprisingly, insulin signaling is implicated in the onset, complication and amelioration of Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD).54 (review) Recently, the alleviating effects of insulin in vivo and in vitro have been discussed. In neuroblastoma cells, expression of amyloid β (Aβ), a pivotal component in the initiation and development of AD, leads to insulin resistance, dysregulation of cholesterol-synthesis gene expression, expression of pro-inflammatory agents and inhibition of anti-inflammatory and neuroprotective agents; these adverse conditions, which interfere with neural function and metabolism, are alleviated by enhanced insulin signaling (induced higher concentration of insulin).55 Regarding lifespan and neurodegeneration in the C. elegans model of hyperglycemia, Insulin prevented both the short lifespan and neuronal impairment following hyperglycemic conditions.56 Furthermore, insulin administration was associated with lower levels of glucose, reactive oxygen species (ROS) and AGEs, and these effects were mediated by both the daf-2/daf-16 pathways and the activity of glyoxalase-1. In humans, the effects of insulin administration were studied using cognitive evaluations such as auditory evoked potentials (AEP), memory testing (word recall and wordstem priming) and the Stroop test, along with mood assessment.57, 58 Insulin administration in these studies, whether intranasally or intravenously, is associated with improved attention, memory and mood; thus the potential for insulin to afford therapeutics in cases of cognitive/insulin deficiencies should be recognized.

Perspectives


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AGEs/RAGE-related neurodegeneration: impairment, amelioration and underlying mechanisms in the C. elegans model When describing hyperglycemic and AGEs-related neurodegeneration, previous studies primarily refer to the C. elegans nervous system as a whole, using general behavioral assays and evaluation of the entire nervous system structure. Neurotransmitter-specific fluorescent tagging and system-specific behavioral assays are used to evaluate structural and functional alteration in different neurotransmitter systems, a few examples being serotonin and pharyngeal pumping, dopamine and egg laying, as well as acetylcholine and locomotor activity.59-63 Applying these methods, the detrimental effects of chronic hyperglycemia and accumulation of AGEs might be more comprehensively explained. Furthermore, implementation of these methods will facilitate the evaluation of insulin as a protective agent against neurodegeneration and the elucidation of pertinent pathways. daf-16 is most commonly studied by using mutant worms, RNA interference (RNAi) and evaluation of its spatial expression (cytoplasm vs. nucleus). Recent studies, however, emphasize the importance of its temporal-spatial expression during development (where is it expressed and at what developmental stage?). A dramatic increase of daf-16 expression, specifically in the young adult stage, is a key factor in C. elegans longevity.64 Studying these aspects, and their correlation with neurodegeneration, will contribute to a better understanding of the onset, development as well as amelioration of hyperglycemia/AGEs-related impairments. In mammals, FOXO transcription factors are related to growth control, DNA repair, apoptosis and oxidative stress.65-67 Data regarding the role of these transcription factors in human longevity have been gradually obtained, enhancing the relevance and applicability of the C. elegans model for studies on longevity and its regulating mechanisms.68-73 Some of these transcription factors, namely FOXO1 and FOXO4, modulate the adverse effects of AGEs/RAGE interaction. The nuclear accumulation of FOXO1 is



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induced by AGEs/RAGE interaction and affects insulin secretion, while activation of FOXO4 is induced by AGEs/RAGE interaction and affects podocyte apoptosis.74, 75 Being exclusively mammalian, RAGE is currently being studied only in mammalian in vivo and in vitro models.76 However, since the C. elegans model is genetically malleable and has been used in the past to express human proteins,77, 78 it could serve as a valuable model for the study of AGEs/RAGE-related neurodegeneration, the role of daf-16 in its underlying mechanisms and the role of insulin in its amelioration. In the race for a better characterization of human neurodegenerative diseases and the development of efficient therapeutics, the mammalian models are exceedingly time and resource consuming. The C. elegans model is evolutionarily distant from humans, nevertheless it shares various structural and functional similarities with vertebrates, such as ion channels, receptors, vesicular transporters and several neurotransmitter systems (serotonin, dopamine, glutamate, GABA and acetylcholine);79, 80 indeed, the C. elegans model was used to describe the pathology of neurodegenerative diseases and the efficacy of mitigating agents with regards to AD, ALS, HD, PD and prion disease, to name a few.81-85 The advantages of this model in the field of drug discovery have also been getting increased attention in recent years due to the importance of phenotypic screening. Novel data shows that between 1999 and 2008, most of the therapeutic agents approved by the US Food and Drug Administration, which are categorized as first-in-class drugs with new molecular mechanism of action, were discovered following phenotypic screening (compared to those discovered by the target-based approach).86 Notably, C. elegans is optimally suited for phenotypic screening. In conclusion, there is dire need for progress in the study of AGEs- and RAGE-related pathology due to their implication – both individually and synergistically – in a myriad of diseases. Elucidating germane detrimental pathways, such as insulin signaling and the activation/localization of daf-16/FOXO, and establishing the role of insulin as a therapeutic agent would greatly contribute to the study of various


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neurodegenerative diseases. Given the prominent expedience of the C. elegans model, it is this model which should be at the forefront of this expedition.

Funding sources This review was supported in part by grants from the national Institute of Environmental Health Sciences (NIEHS), R01 ES10563 and R01 ES07331.

Abbreviations Advanced glycation end products (AGEs); multi-ligand AGEs receptor (RAGE); reactive oxygen species (ROS); RNA interference (RNAi); central nervous system (CNS); Alzheimer's disease (AD); Parkinson's disease (PD).

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Author Biographies Adi Pinkas received his Ph.D. from the Hebrew University, Jerusalem, Israel for his study of neurotoxicology, teratology, and stem cell therapy. He is currently a postdoctoral researcher at the Albert Einstein College of Medicine, NY, where he studies neurotoxicology in the C. elegans model, focusing on the adverse effects of heavy metals and advanced glycation end products.

Michael Aschner serves as the Harold and Muriel Block Chair in Molecular Pharmacology at Albert Einstein College of Medicine. He has served on numerous toxicology panels (Institute of Medicine, US Environmental Protection Agency, Center for Disease Control) and is a member of the Neurotoxicology and Alcohol study section (NIH). Research in the lab focuses on the following topics: (1) modulation of C. elegans genes (aat, skn-1, daf-16) that are homologous to mammalian regulators of MeHg uptake and cellular resistance to modify dopaminergic neurodegeneration in response to MeHg exposure; (2) under conditions of MeHg-induced oxidative stress, Nrf2 (a master regulator of antioxidant responses) coordinates the upregulation of cytoprotective genes that combat MeHg-induced oxidative injury, and genetic and biochemical changes that negatively impact Nrf2 function increase MeHg neurotoxicity; and (3) PARK2, a strong PD genetic risk factor, alters neuronal vulnerability to modifiers of cellular Mn status, particularly at the level of mitochondrial dysfunction and oxidative stress. These studies are designed to shed novel mechanistic insight into metal-induced neurodegeneration, identify targets for genetic or pharmacologic modulation of neurodegenerative disorders, increase knowledge of the pathways involved in oxidative stress, and develop improved research models for human disease using knowledge of environmental sciences.



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C. Elegans model insulin

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Longevity & General neuroprotection

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Acetylcholine Glutamate GABA

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RAGE-Related Neurodegeneration: daf-16 ... - ACS Publications

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