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Current Topics in Medicinal Chemistry

ISSN: 1568-0266 eISSN: 1873-5294

BENTHAM S C I E N C E The international

journal for in-depth reviews on Current Topics in

Medicinal Chemistry Impact Factor:2.9

Kazimierz Gąsiorowski

¹

, Barbara Brokos

¹

, Jerzy Leszek

²

, Vadim V. Tarasov

³

, Ghulam Md Ashraf

⁴

and Gjumrakch Aliev

^5,6,*

1Department of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland; ²Clinic of Psychiatry, Wrocław Medical University, Pasteura 10, 50-367 Wrocław, Poland; ³Institute of Pharmacy and Transla- tional Medicine, Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya St., 119991 Moscow, Russia; ⁴King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; ⁵GALLY International Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA; ⁶Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia

A R T I C L E H I S T O R Y

Received: July 14, 2016 Revised: August 25, 2016 Accepted: September, 04, 2016

DOI: 10.2174/1568026617666170103 161233

Abstract: Glucose homeostasis is crucial for neuronal survival, synaptic plasticity, and is indispensa- ble for learning and memory. Reduced sensitivity of cells to insulin and impaired insulin signaling in brain neurons participate in the pathogenesis of Alzheimer disease (AD). The tumor suppressor protein p53 coordinates with multiple cellular pathways in response to DNA damage and cellular stresses. However, prolonged stress conditions unveil deleterious effects of p53-evoked insulin resistance in neurons; enhancement of transcription of pro-oxidant factors, accumulation of toxic metabolites (e.g. ceramide and products of advanced glycation) and ROS-modified cellular components, together with the activation of proapoptotic genes, could finally induce a suicide death program of autophagy/apoptosis in neurons. Recent studies reveal the impact of p53 on expression and processing of several microRNAs (miRs) under DNA damage-inducing conditions. Additionally, the role of miRs in promotion of insulin resistance and type 2 diabetes mellitus has been well documented. De- tailed recognition of the role of p53/miRs crosstalk in driving insulin resistance in AD brains could improve the disease diagnostics and aid future therapy.

Keywords: Alzheimer disease, Insulin resistance, microRNAs, p53 protein, ROS.

INTODUCTION: BRAIN SENSITIVITY TO INSULIN The sensitivity of brain neurons to insulin is still a debat- able issue, since injection of insulin does not increase glucose transport to neurons in the basal level of brain activity.

In this section, we provide some evidence on the role of insulin in support augmented energy requirements of the brain and in diverse neuroprotective and neuromodulatory actions.

Insulin in the brain is predominantly of peripheral, pancreatic origin, being efficiently transported through the blood-brain barrier (BBB) by a specific transport system coupled to insulin receptors (IR) in cerebral microvessels [1]. Also, direct transport of insulin in circumventricular regions lacking a functional BBB was documented [2]. An- other source of the brain insulin could be the central biosynthesis by neurons in the brain. It has been shown that insulin from central source exerts both local and remote actions including regulation of energy metabolism and neuroprotective and neuromodulatory effects, which let us include it to

*Address correspondence to this author at the GALLY International Bio- medical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA; E-mails: [email protected],

[email protected]

family of neuropeptides synthesized and released from the brain cells [1, 3]. Primary cultures of rat brain neurons and astrocytes revealed significant level of insulin synthesis in neurons and astrocytes [4]. In fact, the synthesis of insulin in the brain was described mostly in cell cultures, whereas proofs from in vivo experiments are still weak. However, it was shown that the number of insulin-immunoreactive neurons significantly decreased in cultures of rat brain cells after the addition of cycloheximide (an inhibitor of protein synthesis) to cell culture medium [5]. The above reports con- clude that insulin of peripheral and central sources is present in the brain, where it executes many important functions in the support of energy homeostasis, and in neuroprotection and neuromodulation.

Although blood-borne glucose is considered the major nutrient in the brain, neurons also use lactate, fatty acids and ketone bodies for their energy metabolism. Glucose, lactate and ketone bodies are taken up from circulation and from perineuronal space by astrocyte transporters. Within astrocytes, glucose is stored as glycogen, lactate is synthesized in the pathway of glycolysis, and ketones arise in fatty acid metabolism [6]. Like glucose, lactate and ketone bodies are also transported within the brain by astrocytes [6]. It seems

Current Topics in Medicinal Chemistry, 2017, 17, 1429-1437

REVIEW ARTICLE

Insulin Resistance in Alzheimer Disease: p53 and MicroRNAs as Impor- tant Players

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that astrocyte metabolic trinity: glucose–glycogen–lactate is crucial for energy homeostasis of the brain [7]. Astrocytes also express ion pump glutamate transporters, which is crucial for modulation of glutamate turnover in the brain and decrease of glutamate excitotoxicity, as well as for the enhancement of lactate synthesis through the activation of gly- colytic pathways by glutamate present in astrocytes [6]. As- trocytes express the IR; in primary cultures of human astrocytes a strong effect of insulin on glucose incorporation to glycogen, as well as insulin dose-dependent increase of astrocyte proliferation were documented [8]. Therefore, it could be pointed out that astrocytes are insulin-dependent cells and correct insulin signaling is necessary for their normal function.

The brain neurons, unlike peripheral tissue, have a con- tinuous requirement for energy substrates. Basal glucose delivery to the brain neurons is supported by insulin independent-glucose transporters GLUT 3 and GLUT 1 [9].

However, increased activity of neurons (cognitive processes, attention, learning, memory formation, motor function release) markedly increases the requirement for glucose, which cannot be provided by GLUT 3 and GLUT 1 [10]. Therefore, a rapid and significant increase of expression of insulin- dependent transporter GLUT 4 is necessary to facilitate glucose uptake in the course of increased neuronal function such as during cognitive activity [10]. Thus, insulin action on brain has a major effect on support higher energy expen- diture connected with increased neuronal activity both by enhanced glucose transport to neurons, and indirectly by assertion of astrocyte glycogen stores which could deliver additional portion of glucose and lactate to neurons.

Together with the regulation of brain energy requirements insulin also exerts significant impact on neuronal functions, being a key neuromodulator involved in cognitive processes, attention, learning and memory [11-14]. IR signaling is important for neuronal development, dendritic outgrowth, neuronal survival, circuit development, synaptic plasticity and postsynaptic neurotransmitter receptor trafficking [15-17]. Like leptin, insulin also targets hypothalamic neurons to control energy homeostasis and feeding behavior [18]. And independent of their anorexigenic effects, insulin and leptin decrease food reward behaviors, thus modulating the function of dopaminergic neurotransmitter systems of the mesolimbic reward system [18]. Insulin inhibits neuronal apoptosis through the activation of protein kinase B in vitro, regulation phosphorylation of tau protein, metabolism of the amyloid precursor protein (APP) and clearance of amyloid-β (Aβ) from the brain in vivo [18]. This indicates that disturbed neuronal IR signaling is involved in the development of neurodegenerative disorders. Undoubtedly, the brain should be perceived as an insulin-sensitive organ with widespread, although selective expression of IR in the olfactory bulb and related limbic structures, thalamus and hypothalamus, hippocampus, cerebellum, amygdala and cerebral cortex [17]. Hence, a proper IR signaling is important for vital function of the brain.

INSULIN AND INSULIN RESISTANCE IN ALZ- HEIMER'S DISEASE (AD)

The cause of AD has not been fully established, however a close correlation between sporadic AD and diabetes melli-

tus is well documented [19-23]. Consistent with the observa- tion that patient with type 2 diabetes mellitus (T2DM) and insulin resistance are at an increased risk of getting AD, decreased insulin levels, lowered IR expression and deficient downstream signaling pathways have been reported to occur in the brains of AD patients [24-26]. A vast number of papers suggest that adding more insulin to brain would improve memory and cell damage.

Insulin deficiency facilitated cerebral β -amyloidogenesis in 5XFAD mouse brains accompanied by significant eleva- tions in β-secretase (BACE-1) and APP expression in the absence of changes in levels of α - and γ-secretase or Aβ- degrading enzymes [27]. Reduced sensitivity of cells to insulin and impaired insulin signaling in brain neurons participates in the pathogenesis of AD.

Among the factors which could influence on neuronal sensitivity to insulin is the p53, a major cellular stress- responsive protein, which coordinates multiple pathways after DNA damage and oxidative and metabolic cellular stresses [28]. However, stressors of various origin and of moderate strength and prolonged duration enhance p53 expression and stability, and unveil deleterious effects of p53:

augmentation of insulin resistance, enhancement of pro- oxidant transcription factors, accumulation of toxic metabolites (e.g.: ceramide, products of advanced glycation), which in concert with activation of proapoptotic genes, could finally induce a suicide death program of autophagy/apoptosis in neurons [29].

Recent studies reveal the impact of p53 on expression and processing of several microRNAs (miRs) in cellular stress conditions [30-34]. Since the role of miRs in promotion of insulin resistance and in T2DM have been well documented [35-37], it is important to recognize a role of p53/miRs crosstalk in driving insulin resistance in AD brains.

ADVANCED GLYCATION END PRODUCTS (AGEs) IN DIABETES AND AD

Both diabetes and AD are associated with increased oxidative stress and intense production of AGEs. Although the association between vascular dementia and AGEs is well established, new research points to a link between AGEs and AD [21, 38]. AGEs have been found in retinal vessels, peripheral nerves, kidneys, and the CNS of diabetics [39].

AGEs couple with free radicals and create oxidative damage, which in turn leads to cellular injury [40]. Hence, diabetic patients could have an increased risk of AD via AGEs production. Oxidative stress on its own also causes AGEs, creat- ing a vicious cycle. AGEs are also known to modify plaques and neurofibrillary tangles (NFTs), both implicated in AD [41]. AGEs have been identified in NFTs and senile plaques.

Since T2DM accelerates the production of AGEs, it may be another causative factor in the development of AD. Thus, the measurement of toxic AGEs in the serum or cerebrospinal fluid (CSF) could be a potential biomarker for early detec- tion of AD [42-44].

INSULIN AND THE CHOLINERGIC HYPOTHESIS The cholinergic hypothesis suggests that AD is caused by an inadequate production of acetylcholine [45-47]. This

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mechanism may also have links to blood sugar abnormalities and insulin resistance. Insulin participates significantly in neurological function by stimulating the expression of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine synthesis [27]. Impairments in growth factor and growth factor receptor expression and function were associated with increasing Braak stage of AD, reductions of insulin, insulin-like growth factor (IGF)-I and IGF-II binding to cellular receptors, and decrease of ATP level [48]. ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons [49]. It was documented that ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD [25, 26]. Therefore, suboptimal insulin levels as well as poor IR sensitivity and disturbed signaling through IR can ultimately contribute to a decrease in acetylcholine [25, 26, 50].Decreased insulin surveillance of glucose metabolism alters neuronal metabolism, for instance, it diminishes activity of pyruvate dehydrogenase, which in turn lowers acetyl coenzyme A level and causes decrease of acetylcholine synthesis [51, 52].

p53 AS A KEY PLAYER IN NEURONAL RESPONSE TO STRESS

The p53 tumor suppressor and nuclear transcription factor regulates major cellular functions, like DNA synthesis and DNA repair, gene transcription, cell cycle, cellular senescence program, and cell death by apoptosis [53]. In post- mitotic neurons p53 can be activated by various cell stressors such as hypoxia, oxidative stress, viral infections, metabolic stress and trophic factor withdrawal, hypoglycemia and hyperglycemia, various insults which lead to DNA damage, oncogene activation, and excitotoxicity [53-55]. According to severity of the stress signal p53 protein helps in cell adaptive response, starts up insulin resistance, or finally triggers cell death program [32].

It is now clear that p53 plays an important role in neurodegeneration, and many studies reported neuronal cell death being associated with increased level of p53 in brain tissue cells [55-57]. Recently, the important function of p53 in regulation of cellular metabolic homeostasis has been revealed. By activation of its target transcription genes p53 contributes to the regulation of glycolysis, glutaminolysis, oxidative phosphorylation, insulin sensitivity, fatty acid oxidation, antioxidant activity, autophagy and mitochondrial integrity [58, 59]. Metabolic stress of mild and moderate strength are regular feature of cell fate and usually triggers p53-mediated adaptive response that helps cell to maintain optimal glucose metabolism and efficient mitochondrial respiration in response to ATP deficiency and to tune up the antioxidant defense mechanisms [59]. However, more potent metabolic stresses could induce p53 to drive cellular death program [24, 60, 61].

Brain neurons are frequently exposed to metabolic and oxidative stresses, usually of mild and moderate intensity, and display mitochondrial failure and glutathione cycle dysregulation, which could lead to neuronal damage and cell death [62-65]. It is well documented that over-nutrition (obesity, T2DM) as well as starvation, and hypoglycemia as well as hyperglycemia lead to neuronal damage by induction of intracellular metabolic stress, changes of redox status in neu-

rons, increase of free radical level and glutamate excitotoxicity [66, 67]. The answer of cells exposed to metabolic stress is an increase of p53 expression to countervail deleterious stress condition, rearrange the main metabolic pathways to boost mitochondrial oxidative phosphorylation and sustain efficient ATP production.

p53 IN DEVELOPMENT OF INSULIN RESISTANCE The major p53 target genes involved in modulation of energy metabolism are TIGAR (TP53-induced glycolysis and apoptosis regulator) and SCO2 (Synthesis of cytochrome c oxidase 2) [68]. TIGAR protein lower the intracellular level of fructose-2,6,-bisphosphate, which results in decreasing glycolysis and directing glucose to an alternative pathway, the pentose phosphate pathway, that produces more NADPH. The SCO2 protein is an important regulator of cytochrome c oxidase complex which enhances mitochondrial respiration. Additionally, p53 lowers transcriptional expression of phosphoglycerate mutase (PGM) thereby switching off its enhancing activity on glycolysis pathway. p53 also directly repress the transcriptional expression of glucose transporters GLUT 1 and GLUT 4 and indirectly reduces the expression of GLUT 3 by negative regulation of the NF-кB pathway [68]. Protein p53 has significant influence on cellular glutaminolytic pathway as it increases expression of glutaminase 2 (GLS2 gene), which encodes a mitochondrial glutaminase, the enzyme that catalyzes the hydrolysis of glutamine to glutamate. GLS2 participates in regulation of cellular energy metabolism by increasing production of glutamate and α -ketoglutarate in mitochondria, which leads to enhanced mitochondrial respiration and ATP generation and also causes an increased level of reduced glutathione (GSH), which protect cells from oxidative stress and oxidative stress-induced apoptosis [69]. Since the influence of p53 on glucose metabolism is opposite to the effects of insulin, it could be pointed out that p53 evokes insulin resistance condition.

LIPID METABOLISM AND INSULIN RESISTANCE – THE ROLE OF p53

Recent findings reveal a major role of p53 in the regulation of lipid metabolism by transcriptional activation of many genes that participate in lipid metabolism; thereby it leads to enhanced lipid catabolism and decreased anabolism of intracellular lipids [70]. It is demonstrated that glucose deprivation leads to p53–induced LIPIN1 gene expression, and LIPIN1 cooperates with two transcriptional regulators (PPARα – peroxisome proliferator–activated receptor α and PGC-1α –peroxisome proliferator-activated receptor gamma-coactivator 1α), which induce the expression of genes involved in enhancing fatty acid oxidation and inhibit- ing fatty acid synthesis [71, 72].p53 also directly activates key proteins involved in fatty acid oxidation, such as carnitine acyltransferases (which catalyze the conjugation of fatty acids to carnitine thereby mediating their transport to the mitochondrion for β -oxidation) and cytochromes P450- 4F2 and P450-4F3 (that catalyze hydroxylation of long-chain fatty acids allowing them enter the β -oxidation pathways) [70]. Inhibitory influence on lipid synthesis is an effect of p53-mediated inhibition of glucose-6-phosphate dehydrogenase (it causes decreased availability of NADPH, which

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lower fatty acid synthesis) and represses expression of SREBP transcription factors (sterol regulatory element–

binding proteins, important regulators of cellular lipogene- sis) [70, 72]. Probably due to the inhibition of glucose-6- phosphatase and diminution of NADPH, the p53 decreases lipid accumulation and thus could be an attractive therapeutic target for various lipid metabolic disorders as obesity, atheromatosis, diabetes and hepatic steatosis [71].

It was also established that p53 exerts significant impact on intracellular sphingolipid metabolism; it induces expression of ceramide synthases, and inhibits sphingosine kinase expression and activity [73]. Elevated intracellular concentration of ceramide could induce cellular senescence program and apoptosis [70, 73]. Ceramide also leads to marked inhibition of IR and IR transduction pathways [74, 75]. For instance, it is well established that ceramide suppress tyrosine phosphorylation and activation of insulin receptors substrate (IRS)-1, inhibits major kinases of insulin signal transduction:

PKB/Akt and PI3-kinase, also activates protein phosphatase 2A (PP2A), which drives dephosphorylation of PKB/Akt, thereby hampering activity of the enzyme [74]. Some authors emphasize that ceramide action paves the way for insulin resistance [75].

In conclusion, the regulation of lipid metabolism by p53 has been established [70-72, 76, 77] although the precise mechanisms, tissue specificity, stress-induced or basal activation, need to be elucidated. However, it should be stressed that the influence of above listed effects of p53 on lipid metabolism are opposite to those exerted by insulin and are in agreement with general picture of p53-induced insulin resistance.

EVIDENCE FOR PARTICIPATION OF p53 IN NEU- RODEGENERATION

Diverse insults could induce apoptotic death program in neurons [56, 57, 78]. On the other hand, normal physiological function of p53 is required for homeostatic regulation of energy-producing processes, coordination of overall rate of biosynthesis, and mobilization of cellular antioxidative defense mechanisms, which enable axonal outgrowth and axonal regeneration [79]. Lack of p53 or its abnormal folding affects neuronal function, leading to neuronal dysfunction [80-82]. p53 transactivates neuronal growth-associated protein-43 (GAP-43), a protein engaged in axonal growth and formation of new connections, and downregulation of GAP- 43 expression is perceived as important molecular lesion that progresses with synaptic disconnections and neurodegeneration [83]. It is worth noticing that exposure of AD fibroblast cultures to low (nanomolar) concentrations of Aβ 1-40 pep- tide induced expression of aberrantly-folded p53; unfolded p53 could participate to early pathogenesis of AD and would be a specific marker of early stage of the disease [82]. To- gether, data cited above accentuate the role of basal p53 level in physiological regulation of metabolic, antioxidant and regenerative processes.

On the other hand, increased p53 expression induced by various moderate chronic cellular stressors leads to significant changes of cellular metabolism, suppression of insulin signaling and expression of pro-oxidant target proteins (p53- inducible genes: PIG3, PIG8, ferredoxin reductase-DRX),

and these changes markedly contribute to progression of neurodegeneration [79].

Recent papers feature the role of p53 interaction with glycogen synthase kinase-3β (GSK3) in regulation of glucose metabolism; the activity of both p53 and GSK3 increases as a result of their interaction [84, 85]. GSK3 is a constitutively active serine/threonine kinase, abundant in the brain, which phosphorylates a broad range of substrates, including enzymes involved in regulation of body metabolism.

Increased expression and activity of GSK3 was found in both sporadic and familiar form of AD and the kinase promotes intrinsic apoptotic pathway in neurons induced by Aβ [86, 87]. GSK3 is engaged in development of insulin resistance, mainly by phosphorylation and inhibition of glycogen synthase but also by modulation of activity of several transcription factors involved in insulin signaling and glucose homeostasis (NF-кB, β -catenin, cAMP response element- binding protein/CREB) [88]. Binding of p53 directly increases activity of GSK3β and, conversely, activated GSK3β enhances the transcriptional activity of p53. This tandem of proteins closely cooperate both in developing insulin resistance and in driving the apoptotic death program, when intracellular level of deleterious metabolites (e.g. ROS, advanced glycation end-products, ceramide) exceeds cellular ability to survive.

MICRORNAs AND THEIR CROSSTALK TO p53 IN CELL RESPONSE TO STRESS

MicroRNAs are single-stranded, small (19-23 nucleo- tides), endogenous, non-coding RNAs that regulate gene expression in eukaryotic cells by inducing translational arrest and degradation of messenger RNAs [89, 90]. miRs are pro- posed to allow organisms and cells to effectively deal with stress [91, 92]. In response to stress, cells adapt by altering their gene expression programs, upregulating a subset of messenger RNAs (mRNAs), which modulate the existing pool of mRNAs without any de novo synthesis, that is, by selectively translating certain mRNAs while halting translation of the rest [93]. Since miRs can also modulate the translation and/or stability of multiple targeted transcripts, it is assumed that miRs play an important regulatory role in coping with a spectrum of stresses like oxidative stress, nutrient deprivation, DNA damage, and oncogenic stress [30, 93-96].

The biological functions of miRs depend on the cellular con- text, i.e. on the differential expression of their target mRNAs in various cells. It regulates the expression not only of protein-coding genes but also of non-coding miRs, which act as mediators of p53 impact on gene expression, and, interest- ingly, also the expression and activity of p53 itself is under the control of miRs [30]. In response to stress, p53 regulates miRs synthesis and maturation, and the miRs participate in diverse cellular regulatory loops that modulate appropriate cellular adaptation [30]. The transcription-independent modulation of miRs biogenesis-maturation and stability en- ables fine-tuning of cellular response to DNA damage and to other stresses of various origin through p53 interaction with the processing complex (the Drosha complex), [97, 98].

Likewise, transcriptionally inactive p53 mutants could inter- act with the Drosha complex leading to attenuation of several miRs processing [98].

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Fig. (1). MicroRNAs (miRs) in regulation of insulin signal transduction.

As p53 is a key player in response to different types of cellular stress, its influence on several aspects of cell adaptation comprises a metabolic shift in cells exposed to stress.

The important executor of the p53 action on stressed cell is the miRs network, and crosstalk between p53 and miRs induction and processing are important to maintain cellular homeostasis.

INSULIN RESISTANCE AND miR’s

MicroRNAs exert major impact on glucose homeostasis and development of T1DM, insulin resistance and T2DM [99, 100]. In TIDM a large number of miRs have been rec- ognized as important factors of pancreatic islets (and therefore β -cell) development and involved in insulin gene expression and hormone release from β -cells [100]. For instance, miR-375 target genes that negatively regulate cellular growth and proliferation, and the aberrant loss of this miR leads to marked reduction of β-cell mass leading to low level of insulin, hyperglycemia and diabetes [100]. The other miRs which play a critical role in insulin exocytosis from β- cells are: miR-9, miR-96 and miR124a [100]. Expressions of the receptor for insulin and IGFs as well as intracellular signal transduction pathways are regulated by miR-143, miR- 145, miR-27b, miR-29a, miR-130, miR-181b, miR-320, miR-519d, miR-320 and miR-383 [101, 102]. Experiments in transgenic mice showed that members of Let-7 family of miRs were also profoundly engaged in glucose homeostasis and insulin resistance, and overexpression of Let-7 resulted in impaired glucose tolerance and reduced insulin secretion [103].

Surprisingly, it was described that miR-7, miR-124a and miR-375 are expressed both in brain tissue neurons and in pancreatic β -cells. Both neurons and β -cells exhibit similar

insulin secretion mechanisms and respond to signals from the bloodstream including glucose and insulin; therefore it is likely that miRs expression in the brain is affected by diabetes, which leads to profound neurologic consequences of such dysregulation [99].

The role of miRs in development of insulin resistance and of T2DM is not yet fully understood, although many important examples have been described. We have outlined several miRs with established impact on insulin transduction pathways. As can be seen in Fig. (1), all major proteins involved in signal transduction from IR are regulated by miRs- modulating translation and hence expression of proteins engaged in the pathway. Specific description of the role of miRs in the development of insulin resistance is now well documented [99, 100, 104]. In Fig. (1), we have marked only those miRs for which the impact on insulin signaling pathways is well established and which could be applied to early diagnostic of insulin resistance and to the elaboration of future therapeutic strategy [104].

p53 INFLUENCE ON miR-REGULATED INSULIN RESISTANCE IN THE BRAIN

Several well-documented studies show a role of p53 impact on miRs in the development of insulin resistance in brain. For instance, it was established that p53 closely regulates miR-34 family of small RNAs [105] and that miR-34a expression, although observed in all tissues, is highest in the brain [31]. Enhanced ectopic expression of miR-34 induces apoptosis, cell-cycle arrest or cellular senescence [31]. It was established that miR-34 regulates age-associated events and long-term integrity of the brain in Drosophila, providing a molecular link between aging and neurodegeneration [106, 107]. Specifically, loss of miR-34 gene triggers a gene pro- i n s u l i n

caweolin-1 or clathrin

nucleus

(transcription)

MAPK

glucose transport

GLUT4

RAS (Rab, Rac1)

PKB/Akt PI3K 1A IRS 1/2 Grb2

miR-133a, miR-133b, miR-223, miR-21, miR-143

P P

miR-103, miR-107 miR-146a

miR-128a, miR-96, miR-126, miR-144, miR-135a miR-183 , miR-96 , miR-182

miR-29, miR-320, miR-126, miR-384-5p, miR-19a, miR-1

miR-143, miR-29, miR-153, miR-33a, miR-33b

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file of accelerated brain aging, late-onset neurodegeneration and a marked decline of survival; whereas a normal level of miR-34 expression plays a neuroprotective role in Droso- phila aging brain [106, 107]. It is believed that the p53/miR- 34 axis exerts regulatory function on cellular metabolism by activation of important target genes: lactate dehydrogenase A (LDHA), sirtuin 1 (SIRT1) and transcription factor cMYC [105].

The miRs profile of insulin resistance tissues changes years before the onset and/or diagnosis of the disease. For instance, a plasma signature of five miRs (miR-15a, miR29b, miR-126, miR-223, and miR-28-3p) can precisely differenti- ate patients with high risk of developing diabetes as com- pared to healthy persons [108], and decreased expression of plasma miR-126 emerges as early biomarker for prediction of T2DM in susceptible people [109].

POTENTIAL ROLE OF EXOSOMES IN SPREADING INSULIN RESISTANCE WITHIN THE BRAIN

Since miRs are released from cells to body fluids in exo- cytotic vesicles - exosomes, it is important to evaluate a profile of neuronal miRs released to blood and/or to CSF in insulin resistant and diabetic patients. Exosomes are taken up by endocytosis to target/recipient cells also with the miRs present in exosomes incorporating exosomal cargo into pathways of recipient cells [110, 111]. Therefore, exosomes could spread pathological components within previously healthy cell (bystander effect). In the brain, exosomes act as crucial messengers in glia-to-neuron reciprocal communication, and are responsible for neuroprotection as well as neurodegeneration. It was documented that exosomes transport various miRs as well as proteins engaged in the development of neurodegeneration such as APP, BACE-1, Aβ, P-tau, α - synuclein, superoxide dismutase (SOD), prion protein PrP [112-115]. They also transport insulin adaptor/substrates, proteins IRS 1 and IRS 2, which are aberrantly phosphorylated in people with insulin resistance and T2DM [116]. It is very probable, albeit not documented by now, that exosomes could transfer miRs engaged in the development of insulin resistance. Importantly, it is well documented that p53 protein enhances secretion of exosomes by upregulation of transcription of proteins involved in cellular vesicle formation and trafficking [117, 118], and these actions are markedly increased by p53 activation during cellular stress response [117]. Undoubtedly, better understanding of mechanisms of neurodegeneration and the role of insulin resistance in the development of neurodegeneration need further knowledge on exosome formation, content of their cargo and conditions of spreading pathogenic messengers between glia and neurons within the brain.

CONCLUSION

Stressors of various origins and of moderate strength and prolonged duration enhance p53 expression and stability.

Diverse targets activated by p53 inhibit glycolysis and glucose uptake, impede insulin signaling, and enhance fatty acid catabolism which is coordinated with decreased metabolic flux through the tricarboxylic acid (TCA) cycle and impaired oxidative phosphorylation and adenosine triphosphate (ATP) synthesis. The results are opposite to the effects of insulin,

thus resulting in the development of syndrome of insulin resistance syndrome.

In response to stress, p53 regulates miRs synthesis and maturation, and the miRs participate in diverse cellular regulatory loops that modulate appropriate cellular adaptation.

Since miRs can also modulate the translation and/or stability of multiple targeted transcripts, it is assumed that miRs play an important regulatory role in coping with a spectrum of stresses like oxidative stress, nutrient deprivation, DNA damage, and oncogenic stress. p53/miRs regulatory axis is important in maintaining homeostasis in organisms and cells exposed to various stress conditions. Aberrant expression of p53/ miRs axis leads to the development of diseases like insulin resistance and T2DM, and frequently causes im- proper cell cycle regulation, cell differentiation, and apoptosis regulation, and finally could lead to cancer.

Future research on the regulation of p53/miRs axis and their influence on exosome formation and their cargo content could provide significant improvement of repertoire of early diagnostic biomarkers, and will also open a new avenue for the treatment of neurodegeneration.

LIST OF ABBREVIATIONS

AGEs = Advanced Glycation End Products AD = Alzheimer Disease

ATP = Adenosine Triphosphate

Aβ = Amyloid-β

APP = Amyloid Precursor Protein BBB = Blood Brain Barrier ChAT = Choline Acetyltransferase CSF = Cerebrospinal Fluid

GSK3 = Glycogen Synthase Kinase-3β IGF = Insulin-Like Growth Factor IR = Insulin Receptors

IRS = Insulin Receptors Substrate miRs = microRNAs

TCA = Tricarboxylic Acid T2DM = Type 2 Diabetes Mellitus CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

This work partly supported by the Russian Scientific Foundation (www.rscf.ru, Российский Научный Фонд, Grant № 14-23-00160 for 2014-2016: Directed design, synthesis, and study of biological activity of multi-target compounds as innovative drugs for treatment of neurodegenerative diseases).

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