The Role of Protein S-nitrosylationin Alzheimer’s disease and its Treatment

As a post-transcriptional modification, S-nitrosylation is a covalent binding of nitric oxide to cysteine thiols in proteins to form S-nitrosothiols. Nitric oxide is recognized as an important signaling molecule, and has recently been shown to reversibly nitrosylated proteins. Emerging evidence demonstrates that in Alzheimer’s disease, aberrant S-nitrosylation of proteins may exert an effect on mitochondrial fission, Aβ production and synaptic damage, which may directly or indirectly contribute to Alzheimer’s disease pathology. In this paper, we review recent findings of an S-nitrosylated protein relationship to the pathogenesis of Alzheimer’s disease; discuss the influences of protein S-nitrosylation on Alzheimer’s disease progression; and consider indications for protein S-nitrosylation in the treatment of Alzheimer’s disease. Alzheimer’s disease (AD) is the most common and leading form of dementia in the aged population, accounting for an estimated 6080% of all cases [1]. In the United States, approximately 5 million people now suffer from AD, with a 50% increase expected by the year 2025 [2]. AD is recognized as a neurodegenerative disorder although its etiology is not yet fully understood. The majority of AD cases are sporadic, which has a rare relationship with heritance, [3] and only a small proportion of cases are familial, mainly attributed to three genes: β-amyloid precursor protein (APP), presenilin 1 and presenilin 2. A vast amount of cell injury and loss occur in various parts of the brain of patients with AD, particularly in the hippocampus and neocortex [4]. One of the most common characteristics of AD pathogenesis is synaptic deficit, which attributes to intellectual and cognitive decline [5,6]. AD patients experience overwhelming memory loss, cognitive impairment and behavioral changes like aphasia, apraxia, agnosia and executive dysfunction. Currently there is no cure and palliative treatment options are limited. Irrespective of genetics, advancing age is the leading factor associated with AD, with the fact that people over 65 years of age are far more likely to have the disease. Neuropathology of Alzheimer’s Disease Although the mechanisms of AD are not fully understood, Aβ plaque, neurofibrillary tangles and neurotransmission deficits have been identified to be its main characteristics [7-9]. Aβ plaque results from aggregation of Aβ peptides that originate from cleavage of APP by β-secretase and γ-secretase [7]. It has been found that Aβ oligomers are toxic, and can cause synapse loss and neuronal cell death [10]. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins in the brain [11]. Tau protein is expressed in axons and binds to tubulin, which stabilizes microtubules. In AD patients, hyperphosphorylated tau protein aggregates into insoluble tangles, which have a detrimental effect on the transport system of neurons, resulting in disconnection of neurons and eventually cell death [8,9]. Since AD is an age-dependent disease that mainly occurs in the elderly, ageing is a leading factor. The free radicals that can cause oxidative/nitrosative stress contribute significantly to the aging process. Indeed, many studies have reported that the AD brain exhibits increased oxidative/nitrosative stress [12]. Increasing evidence suggests that protein S-nitrosylation plays an important role in the pathophysiological development of AD [13,14]. The glutamatergic and cholinergic systems are highly involved in memory and cognition. Dysregulation of these two systems is implicated in the progression of AD [15,16]. Glutamate is the main excitatory neurotransmitter in the central nervous system. Hyperactivation of N-methyl-D-aspartate (NMDA) glutamate receptor mediates excitotoxicity that contributes to AD pathology [15]. Non-competitive NMDA receptor antagonist memantine is currently used for the treatment of moderate-to-severe AD [17]. Degeneration of cholinergic neurons in basal forebrain has long been reported in AD patients [18], and cholinergic deficits lead to reduced synthesis of acetylcholine [18]. Therefore, a category of currently available drugs for mild to moderate stage of AD are used to enhance acetylcholine levels in the brain, including, for instance, donepezil, rivastigmine and galantamine [19]. Nitric Oxide and Protein S-nitrosylation Nitric oxide (NO) is produced from L-arginine catalyzed by nitric oxide synthases (NOS) including endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) [16,20,21]. This process also requires cofactors/coenzymes such as nicotinamide adenine dinucleotide phosphate, flavine mononucleotide and flavin adenine dinucleotide [22,23]. NO participates in various cellular signaling pathways to regulate a spectrum of brain functions such as neuronal development, synaptic plasticity and apoptosis [24,25]. The actions of NO are multifaceted and mainly classified into two categories: cyclic guanosine monophosphate (cGMP) dependent actions and cGMPindependent actions [26]. Studies have shown that NO at nano molar concentrations is sufficient enough to activate guanylate cyclase and trigger cGMP-dependent signals [26]. NO activated cGMP has been recognized to play critical roles in NO-mediated vasodilation [27]. In addition, NO/cGMP also contributes to the immune system, Ying Wang1,2 and Jun-Feng Wang1,2* 1Kleysen Institute for Advanced Medicine, Winnipeg Health Sciences Centre, Canada 2Departments of Pharmacology and Therapeutics, and Psychiatry, University of Manitoba, Winnipeg, Canada Address for Correspondence Jun-Feng Wang, Departments of Pharmacology and Therapeutics, and Psychiatry, University of Manitoba, Winnipeg, Canada, E-mail: [email protected] Submission: 02 February 2015 Accepted: 07 March 2015 Published: 12 March 2015 Review Article Open Access Journal of Pharmaceutics & Pharmacology Avens Publishing Group Inviting Innovations Avens Publishing Group Inviting Innovations Copyright: © 2015 Wang Y, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Citation: Wang Y, Wang JF. The Role of Protein S-Nitrosylationin Alzheimer’s Disease and its Treatment. J Pharmaceu Pharmacol. 2015;3(1): 6. J Pharmaceu Pharmacol 3(1): 6 (2015) Page 02 ISSN: 2327-204X neurotransmission processes and regulation of cardiac contractility [28-30]. NO at higher than 50-100 μM can modify the thiol group of cysteine residues in proteins via covalently binding and induce protein cysteine S-nitrosylation [26,31-36]. Like other posttranslational modifications, S-nitrosylation is able to trigger conformational changes of various proteins. S-nitrosylatedthiols in cysteine residues can be reduced back to free thiols by glutathioneorthioredoxin [37]. For instance, S-nitrosothiol group can be denitrosylated by glutathione, forming a reduced protein thiol and S-nitrosoglutathione. S-nitrosoglutathione is rapidly and irreversibly metabolized by S-nitrosoglutathione reductase to glutathione S-hydroxysulfenamide. S-nitrosylatedthiols can also be denitrosylated by thioredoxin through its dithiol moiety to form thioredoxin disulfide and nitroxyl or NO, while thioredoxin disulfidecan be reduced back to thioredoxin by thioredoxin disulfide reductase [37]. Cysteine residues in proteins are critical in regulating enzymes, transcription factors, protein structures and metal binding. Thiols of cysteine residues are very susceptible to be oxidatively modified by NO radicals. In AD, Aβ toxicity can cause the hyperactivity of NMDA receptors, resulting in increased Ca2+ influx that activates nNOS and increases NO production [38,39]. In addition, Aβ can increase NO production by activating iNOS in glial cells [25,38,40]. NMDA plays a critical role in the regulation of NO production in AD [41]. Increased NO in AD brains may target a wide variety of proteins. Indeed, many studies have presented compelling evidence implicating NO-induced S-nitrosylation of proteins in the pathogenesis of AD [42-44]. The Role of S-nitrosylation in AD Many studies have shown that protein S-nitrosylation is increased in brain of AD patients. Although the exact mechanism of increased S-nitrosylation protein remains largely unknown, the vast majority of S-nitrosylated proteins are reported to be involved in mitochondrial dysfunction, protein misfolding, synaptic loss and Aβ production (Figure 1). S-nitrosylation on mitochondrial dysfunction Mitochondria are the main production sites for the cellular energy currency adenosine triphosphate. Mitochondrial functioning and energy metabolism are impaired early in the course of AD [45] but this mechanism is not fully understood. It has been reported that excessive S-nitrosylation of mitochondrial proteins may suppress protein functioning, thus compromising, at least partially, mitochondrial functioning, especially in neurodegenerative diseases such as AD where ROS/RNS are overwhelmed at a certain stage of the disease. Recent studies show that S-nitrosylation of dynamin-related protein 1 (Drp1) is increased in AD. Drp1 is responsible for mitochondrial division and involved in regulation of mitochondrial fission. Mitochondrial functioning requires highly intact structure, in which an intricate balance of fusion and fission is a major determinant. Mitochondrial fusion promotes the mixing of organellar contents and unifies the mitochondrial compartment, both of which guarantee the exchange of mitochondrial DNA as well as various metabolites. Therefore, mitochondrial fusion ensures efficient production of adenosine triphosphate [46]. Fission, on the other hand, breaks down the unified mitochondrion into numerous small morphologically and functionally distinct organelles, leading to mitochondrial fragmentation, a signal of apoptosis [47]. Therefore, the imbalance between mitochondrial fusion and fission contributes to neurodegenerative diseases [48]. Drp1 as a dynamin-related guanosine triphosphatase mediates membrane fission through promoting dynamin dimerization and is a core component of the