CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 13, Issue 2, 2014

Developing a single selective ligand to a target relevant to two mechanistically interlinked diseases, such as type 2 diabetes mellitus (T2DM) and a neurodegenerative disorder, like Parkinson’s disease or Alzheimer’s disease, provides the potential for an effective treatment that may impact both. The enzyme 5-lipoxygenase (5-LOX) has been revealed responsible for producing fatty acid molecules, leukotrienes. These leukotrienes are known to produce inflammatory responses in asthma and allergic reactions, to induce a reduction of tyrosine hydroxylase in brain, and are involved in the development of cardiac strokes, obesity and type 2 diabetes. N1-p-fluorobenzyl-cymserine (FBC), an analogue of cymserine and a known cholineterase inhibitor, was evaluated for inhibition of pleiotropic 5-LOX in our study. The stable 3D structure of 5-LOX was obtained from the Protein Data Bank (PDB) database and was implied for homology modeling of four reported mutant models. Each generated model was submitted to the Protein Model Database (PMDB) and employed for measuring inhibition and ligand efficiency of FBC with support of molecular docking. For each model, normal as well as mutant, FBC yielded remarkable inhibition constant values, with exothermic free binding energies. The current study revealed a highly reactive narrow fissure near the non-heme iron binding pocket of 5-LOX that contains residues crucial for 5-LOX stability and FBC binding. Investigating the binding of FBC with stabilized and destabilized 5-LOX structures confirmed it as a candidate therapeutic inhibitor worthy of assessment in preclinical models of T2DM and neurodegeneration.

Alzheimer’s disease (AD) is a major health concern that affects nearly every society worldwide. The disease is an irreversible, progressive and age-related neurodegenerative disorder. It is characterized by impaired cognitive function and the diffuse deposition of amyloid plaques and neurofibrillary tangles. The causes of AD and the underlying mechanisms that trigger the onset of the disease are still a matter of debate. Several epidemiological studies have shown that the development of AD is associated with type 2 diabetes mellitus (T2D). In this review, we provide evidence for the link between T2D and AD, highlighting the critical role of insulin in the pathogenesis of these diseases, and we provide information on the genes that might be involved in the interplay between these two disorders. New insight into the complex biology of AD is necessary for the early diagnosis of the disease, the development of novel drug therapies and the prevention of these health issues.

Alzheimer’s disease (AD) is a progressive neurological disease of the brain leading to the irreversible loss of neurons and intellectual abilities. Diabetes mellitus type 2 (T2DM) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The prevalence of AD and T2DM is increasing at an alarming rate and has become a major public health concern worldwide. The clinico-pathological relationship between AD and T2DM has been debated for more than a decade. Recent epidemiological studies have provided direct evidence that T2DM is a strong risk factor for AD and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD as compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood and therefore are worth intensive research. The existence of proteomic links between AD and diabetes is an important topic currently under active debate. An understanding of the complex association between diabetes and AD is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. This review aims to summarize what is currently known about the biological and especially proteomic relationships and similarities between these two age-related devastating diseases of modern day life. This study may also aid in future for the identification of a single or a panel of potential blood-based protein biomarkers for early diagnosis of AD and T2DM with high sensitivity and specificity.

Epidemiological data testifies the increasing incidence of Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). Some associations were made between occidental lifestyle and development of these pathologies, moreover AD and T2DM are linked since each pathology is a causative risk factor for the other. Interestingly, autophagy, a catabolic pathway whose efficiency declines with age is importantly impaired in the affected tissues. Autophagy regulation is dependent of cell metabolic status and consequently on the 5’AMP-activated protein kinase (AMPK) and mammalian target of rapamycin signaling pathways. These pathways are altered with aging and molecular, pharmacological and physiological interventions increase lifespan in various organismal models and favours healthy aging diminishing the occurrence of age-related diseases such as diabetes, cancer, cardiovascular and neurodegenerative pathologies. Decreasing calorie intake has been known for a long time to have a beneficial effect on longevity and health. Some drug agonists of AMPK are known to mimic these effects such as metformin or resveratrol, a polyphenol extracted from plants and present in red wine, a component of the French paradox related diet. In this review, we present the epidemiological and pathogenesis links existing between AD and T2DM with an insight into the perturbations of the autophagic process highlighting the crucial role of the AMPK in development of age and metabolic related diseases. Hence, in a last part we will discuss the possible interventions susceptible to combat both T2DM and AD.

The relationship between the two age-related diseases namely, Alzheimer's disease (AD) and type II diabetes mellitus (T2DM), is gaining much attention in research because of the alarming forecast on both increasing incidence and economic burden. Recent research studies have identified some of the existing links, between AD and T2DM, such as the dysfunctional glucose metabolism and insulin signaling, stress and inflammation, defective protein processing and the role of advanced glycation end products. It is, therefore, crucial to understand the cellular and molecular mechanisms to identify the common linking mechanisms involved in the pathogenesis of both AD and T2DM. Genome wide association studies may lead to identification of novel targets and provide clues for possible interventional strategies to limit the progression of these two age-related diseases. Hence, the purpose of the present review is to provide an update, on the various possible linking cellular and molecular mechanisms, including our experience on the use of high throughput applications to investigate the molecular mechanisms underneath the neurodegeneration in animal models. Besides, using this knowledge-driven approach, we discuss how the current technological advancements can effectively be used to identify possible associations between these age-related diseases.

Enzymes play a very vital role in maintaining the homeostasis inside the body. Improper functioning of enzymes is associated with many diseases. Insulin-degrading enzyme (IDE), a ubiquitously expressed zinc metalloprotease, is believed to act as a junction point of Type 2 Diabetes and Alzheimer’s disease. Recent studies provide inkling for the use of IDE as a potential target hence the design of its regulators would be a viable approach towards treatment of these diseases. This review provides an overview of the IDE structure and function; a relationship is drawn between IDE, Type 2 Diabetes mellitus and Alzheimer’s disease and the approaches that make IDE a potential target, are discussed.

Several chemotherapeutic drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. This study describes molecular interactions between human brain acetylcholinesterase (AChE) and the well-known anti-neoplastic drug, Cisplatin. Docking between Cisplatin and AChE was performed using ‘GOLD 5.0’ and accessible surface area of protein before and after ligand binding was calculated by NACCESS version 2.1.1. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Cisplatin within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit docking. Gold fitness score of ‘Cisplatin- acyl domain of AChE’ interaction and ‘Cisplatin-CAS domain of AChE’ interaction were 38.78 and 39.91, respectively and free binding energy was found to be -5.82 Kcal/mol and -5.79 Kcal/mol, respectively. During ‘Cisplatin-CAS site of AChE enzyme’ interaction, it was found that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues namely S203 and H447 interact with Cisplatin by hydrogen bonding and hydrophobic interaction, respectively. The values for ‘accessible surface area’ for the amino acid residues H447 and S203 were found to be reduced by 14.398 Å2 and 3.894 Å2, respectively after interaction with Cisplatin. Hence, Cisplatin might act as a potent inhibitor of AChE. Scope still remains in the determination of the three-dimensional structure of AChE-Cisplatin complex by X-ray crystallography to validate the described data. Moreover, such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Cisplatin.

The incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) with associated serious complications continues to grow rapidly especially in developed countries. Emerging evidence indicates that AD and T2DM share some common risk factors with comparable pathological features including insulin resistance, amyloidogenesis, glucocorticoid imbalance, inflammation, mitochondrial function and oxidative stress. T2DM has been identified as a risk factor for AD. It has even been hypothesized that AD might be “type 3 diabetes”. In addition to amyloid precursor protein processing and tau phosphorylation, commonalities between T2DM and AD in molecular mechanisms provide clues to the identification of novel therapeutic targets such as glucagon-like peptide 1, butyrylcholinesterase, and receptor for advanced glycosylation end products. Although several classes of anti-diabetic drugs are available, achieving long-term glycaemic control without side effects is often challenging. This review summarizes recent evidence for the pathological links, common therapeutic targets, currently the U.S. Food and Drug Administration approved and potential future therapies, giving special attention to ongoing clinical trials of antidiabetic drugs in AD patients and common therapeutic strategies in the management of both AD and T2DM.

Cognitive decline is a debilitating feature of Alzheimer’s disease (AD). The causes leading to such impairment are still poorly understood and effective treatments for AD are still unavailable. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for AD due to desensitisation of insulin receptors in the brain. Recent studies have suggested that epigenetic mechanisms may also play a pivotal role in the pathogenesis of both AD and T2DM. This article describes the correlation between AD and T2DM and provides the insights to the epigenetics of AD. Currently, more research is needed to clarify the exact role of epigenetic regulation in the course and development of AD and also in relation to insulin. Research conducted especially in the earlier stages of the disease could provide more insight into its underlying pathophysiology to help in early diagnosis and the development of more effective treatment strategies.

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer’s disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of β-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and β-amyloid peptide (Aβ) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two devastating diseases that are currently incurable. Epidemiological, clinical and pathological evidence has confirmed the co-existence of these two disorders. Moreover, there has been promising progress made in the identification of the pathological linkage between T2DM and AD in the last decade. Hence, developing common treatment strategies for these diseases is important. Currently, enzyme targeting is a potential strategy to cure many diseases. In this communication, we tried to summarize the single enzymetargeted therapeutic approach for the treatment of AD and T2DM. This field of research continues to be active and progressive in identifying many promising enzymes that are involved in both diseases. Based on this review article, we also believe that enzyme inhibition is a promising and reliable strategy for the treatment of many incurable diseases. In the future, we expect that the scientific community will be able to develop common enzyme inhibitors for the treatment of both AD and T2DM.

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer’s disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are complex diseases commonly associated with aging. Accumulating evidence indicates a connection between these two diseases at the molecular level. Much of what we currently know about T2D and AD is derived from in vivo and in vitro studies. However, further research and characterization of molecules is necessary to establish a strong connection between T2D and AD. In silico studies play a major role in finding non-evident patterns of gene expression and gene network connectivity. In this review, we give a brief introduction to T2D and AD and then describe the risk factors and molecules that are commonly associated with these diseases. Finally, we discuss the future directions and applications of bioinformatics that can provide greater insight into the relationship between these two diseases. Analysis and integration of high-throughput data on genomics, transcriptomics, proteomics and metabolomics from normal and disease tissues would be very useful to improve our understanding of the mechanism behind disease initiation and the connection between these two diseases. We encourage researchers to use bioinformatics approaches to identify genes and their regulatory pathways that are commonly affected in T2D and AD, as these genes and pathways could be potential biomarkers and targets for disease treatment.

Recent data suggest that brains of patients with Alzheimer’s disease (AD) are insulin and insulin-like growth factor-1 (IGF-1) resistant. So far, there have been two different approaches to investigate possible therapeutic implications of modulating cerebral insulin/IGF-1 signaling (IIS) in AD. One approach is peripheral or intranasal administration of insulin or IGF-1. Intranasal and peripheral insulin administration has been shown to improve memory in patients with AD. Additionally, peripheral IGF-1 administration resulted in decreased amyloid-beta (Aβ) levels in brains of AD mouse models accompanied by elevated Aβ levels in the cerebrospinal fluid (CSF). Insulin and IGF-1 regulate multicargotransporters influencing trafficking of several molecules including Aβ from the brain to the blood as well as to the CSF and possibly vice versa. Furthermore, insulin and related peptides regulate neurovascular coupling changing regional blood flow. Thus, positive effects of peripheral insulin/IGF-1 administration on AD pathology might be due to changes in the blood-brain-barrier (BBB) and/or in the transport between the CSF/blood and the brain. Clinical and experimental data suggest that increased serum insulin and IGF-1 levels do not necessarily correlate with an upregulation of neuronal insulin/IGF-1 receptor signaling. Therefore, the second approach in investigating the role of neuronal IIS for the pathogenesis of AD analyzes knockout mice lacking components of the IIS in AD models. Haploinsufficiency of the IGF- 1 receptor (IGF-1R) (IGF-1R+/- mice) as well as neuronal deficiency of the insulin receptor (IR) (nIR-/- mice) or IGF-1R (nIGF-1R-/- mice) leads to delayed Aβ accumulation when crossed with mouse models for AD. Furthermore, insulin receptor substrate (IRS)-2 knockout mice (IRS-2-/- mice) show reduced Aβ levels in an Alzheimer background. These data suggest beneficial effects of decreased neuronal IIS on Alzheimer-pathology and question the therapeutic outcome of long-term administration of insulin or IGF-1 in patients with AD. Whether the observed phenomenon of cerebral insulin and IGF-1 resistance even at an early stage of Alzheimer's disease is cause, consequence or possibly counter-regulation to AD-pathology needs further investigation and should lead to critical discussions. The current review discusses the pros and cons of targeting insulin/IGF-1 signaling as therapeutic approach for AD.

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two progressive and devastating health disorders afflicting millions of people worldwide. The probability and incidence of both have increased considerably in recent years consequent to increased longevity and population growth. Progressively more links are being continuously found between inflammation and central nervous system disorders like AD, Parkinson's disease, Huntington's disease, motor neuron disease, multiple sclerosis, stroke, traumatic brain injury and even cancers of the nervous tissue. The depth of the relationship depends on the timing and extent of anti- or pro-inflammatory gene expression. Inflammation has also been implicated in T2DM. Misfolding and fibrillization (of tissue specific and/or non-specific proteins) are features common to both AD and T2DM and are induced by as well as contribute to inflammation and stress (oxidative/ glycation). This review appraises the roles of inflammation and abnormalities in the insulin signaling system as important shared features of T2DM and AD. The capacity of anti-cholinesterases in reducing the level of certain common inflammatory markers in particular if they may provide therapeutic potential to mitigate awry mechanisms leading to AD.

Stress has become an integral part of human life and organisms are being constantly subjected to stress and the ability to cope with such stress is a crucial determinant of health and disease. Neuropeptides (bioactive peptides) play a crucial role in mediating different effects of acute and chronic stress. Some of these neuropeptides including oxytocin, urocortins, neuropeptide Y (NPY), neuropeptide S, cocaine and amphetamine regulated transcript, endorphins, enkephalins, ghrelin and thyrotropin-releasing hormone primarily attenuate stress and act as anxiolytic. On the other hand, neuropeptides including corticotropin releasing hormone, vasopressin, dynorphin, angiotensin, nesfatin-1, orexin and cholecystokinin primarily tend to promote stress related anxiety behavior. However, these neuropeptide tend to produce different actions depending on the type of receptors, the nature and intensity of the stressor. For example, NPY may exhibit anxiolytic effects by activating NPY1 and Y5 receptors, while pro-depressive effects are produced through NPY2 and Y4 receptors. Galanin may produce ‘prodepressive’ effects by activating its Gal 1 receptors and exert ‘antidepressant’ effects through Gal 2 receptors. The present review describes different neuropeptides as therapeutic targets to attenuate stress-induced behavioral and neuroendocrinological effects.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly. In recent years increasing evidence supports the pharmaceutical potential of curcumin, a polyphenolic compound in the spice turmeric, against PD. Here we briefly summarize the pharmacological activities of curcumin in vitro and in animal models of PD, including counteracting oxidative stress and inflammation, preventing α-synuclein aggregation and fibrillation, and inhibiting monoamine oxidase B, which endow curcumin with multiple pharmaceutical activities against PD and encourage further studies to investigate its clinical effects.