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Bronwen Martin, Wayne Chadwick,
Wei-Na Cong,
Nick Pantaleo,
Caitlin M Daimon,
Erin J Golden,
Kevin G Becker,
William H Wood,
Olga D Carlson,
Josephine M Egan,
Stuart Maudsley
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ABSTRACT: Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.
Journal of Biological Chemistry 07/2012; 287(38):31766-82. · 4.77 Impact Factor
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ABSTRACT: The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic (db/db) and nondiabetic wild-type (C57/Bl/6) animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non-diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds.
International Journal of Endocrinology 01/2012; 2012:732975. · 1.87 Impact Factor
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ABSTRACT: As pharmacological data sets become increasingly large and complex, new visual analysis and filtering programs are needed to aid their appreciation. One of the most commonly used methods for visualizing biological data is the Venn diagram. Currently used Venn analysis software often presents multiple problems to biological scientists, in that only a limited number of simultaneous data sets can be analyzed. An improved appreciation of the connectivity between multiple, highly-complex datasets is crucial for the next generation of data analysis of genomic and proteomic data streams. We describe the development of VENNTURE, a program that facilitates visualization of up to six datasets in a user-friendly manner. This program includes versatile output features, where grouped data points can be easily exported into a spreadsheet. To demonstrate its unique experimental utility we applied VENNTURE to a highly complex parallel paradigm, i.e. comparison of multiple G protein-coupled receptor drug dose phosphoproteomic data, in multiple cellular physiological contexts. VENNTURE was able to reliably and simply dissect six complex data sets into easily identifiable groups for straightforward analysis and data output. Applied to complex pharmacological datasets, VENNTURE's improved features and ease of analysis are much improved over currently available Venn diagram programs. VENNTURE enabled the delineation of highly complex patterns of dose-dependent G protein-coupled receptor activity and its dependence on physiological cellular contexts. This study highlights the potential for such a program in fields such as pharmacology, genomics, and bioinformatics.
PLoS ONE 01/2012; 7(5):e36911. · 4.09 Impact Factor
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ABSTRACT: The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.
PLoS ONE 01/2012; 7(5):e36975. · 4.09 Impact Factor
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PLoS ONE 01/2012; 7(5). · 4.09 Impact Factor
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Current Alzheimer research 01/2012; 9(1):1-4. · 4.97 Impact Factor
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ABSTRACT: The extensive prevalence of Alzheimer's disease (AD) places a tremendous burden physiologically, socially and economically upon those directly suffering and those caring for sufferers themselves. Considering the steady increases in numbers of patients diagnosed with Alzheimer's, the number of effective pharmacotherapeutic strategies to tackle the disease is still relatively few. As with many other neurodegenerative mechanisms, AD, is characterized by the continued presence and accumulation of cytotoxic protein aggregates, i.e. of beta-amyloid and the microtubule associated protein, tau. Therefore, one novel therapeutic avenue for the treatment of AD may be the actual targeting of factors that control protein synthesis, packaging and degradation. One of the prime cellular targets that, if effectively modulated, could accomplish this is the endoplasmic reticulum (ER). The ER can not only control cellular protein synthesis, trafficking and degradation but it is also closely associated with cytoprotective mechanisms, including calcium ion regulation and unfolded protein responses. This review will delineate some of the most important functional physiological features of the ER that, if effectively modulated, could result in beneficial amelioration or remediation of the negative cellular aspects of AD initiation and progression. While not a classical drug target, even with minimal levels of beneficial modulation, its multifactorial efficacy may amplify small effects resulting in significant therapeutic efficacy.
Current Alzheimer research 01/2012; 9(1):110-9. · 4.97 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) represents one of the most important future therapeutic targets, both with regards to basic and translational research, due to the progressive aging of most westernized countries. Estimates in 2006 indicated that the worldwide prevalence of AD was nearing 27 million cases [1] and with greater and greater proportions of the world population living beyond 60 years of age, nearly 1 in 85 people worldwide may suffer from AD in the mid-part of this century. The potential economic, social and healthcare burden of a progressive disease of this prevalence clearly presents one of the most important future threats to worldwide health. Since AD currently has no effective therapeutic cure, and it gradually renders people incapable of tending to their own needs, long-term assistive caregiving essentially is the only treatment. The need for this long-term assisted (or `informal') care of AD patients also means that the social and healthcare burden also affects collateral populations and may also detrimentally affect their standard of living. A recent European Union (EU) study was created to focus upon this specific aspect of the socioeconomic burden of AD. In the 2008 Eurocode Study [2], it was estimated that 7.23 million people suffered from dementia in 27 EU countries (EU27) in 2008. The total costs of illness for dementia disorders in the EU27 was estimated to be 160 billion Euros, of which more than half was attributed to the costs of informal healthcare. Considering the tremendous future social and economic threat posed by the increasing prevalence of AD, there are worryingly few new therapeutic strategies to effectively tackle this disease [3]. Many lines of research have focused intently upon issues such as direct disease mechanisms, but have failed thus far to generate any significant therapeutic breakthroughs. Considering the profound prevalence of AD in westernized societies, the current AD pharmacopeia is significantly lacking. Four pharmacotherapeutics are currently approved by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency to treat the cognitive manifestations of AD. Reinforcing the paucity of the range of available and effective AD therapies, three of these four compounds belong to the same drug class, i.e. acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) while the other, memantine, is an N-methyl-D-aspartic acid (NMDA) receptor modulator. In contrast to this limited capacity to treat AD, a similarly prevalent disorder, i.e. hypertension, can be medicated by multiple forms of therapeutic comopounds including, diuretics (e.g. acetazolamide, amiloride), calcium channel blocking agents (e.g. amlodipine, diltiazem), angiotensin converting enzyme inhibitors (e.g. captopril, enalapril), angiotensin receptor II antagonists (e.g. losartan, valsartan), centrallyacting alpha adrenoceptor agonists (e.g. clonidine, doxazosin), catecholamine depleting agents (e.g. reserpine), beta adrenoceptor antagonists (e.g. atenolol, carvedilol) and up to eighteen different forms of combination therapeutics (e.g. amiloriode-hydrochlorothiazide, felodipine-elanapril). Therefore our range of AD therapies is seriously limited. In addition to this rather pessimistic observation, only donepezil is approved for treatment of advanced AD dementia [4]. Unfortunately the use of the anti-AD therapies in cases of mild cognitive impairment (MCI) has failed to demonstrate any significant efficacy in delaying of the onset of AD [5]. In addition to their rather limited therapeutic actions many of the currently approved AD therapies also cause physiological effects likely to reduce drug compliance, i.e. nausea, vomiting, bradycardia, decreased appetite, weight loss and increased gastric acid production and irritation. To combat this current lack of multiple efficacious anti-AD strategies, over four hundred different pharmaceutical agents are currently under investigation around the world, with nearly one hundred of these nearing the later stages of clinical review [6]. The areas of research occupied by these agents currently in development include, agents that reduce amyloid beta through vaccination processes, reduce oxidative stress via metal ion chelation or attenuate the long term inflammatory responses associated with AD [7-10].....
Current Alzheimer Research 12/2011; 9(1):1-4. · 3.95 Impact Factor
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ABSTRACT: The hippocampus mediates the acquisition of spatial memory, but the memory trace is eventually transferred to the cortex. We have investigated transcriptional activation of pathways related to cognitive function in the cortex of the aged mouse by analyzing gene expression following water maze training.
We identified genes that were differentially responsive in aged mice with accurate spatial performance during probe trials or repeated swimming sessions, relative to home cage conditions. Effective learners exhibited significantly greater activation of several pathways, such as the mitogen-activated protein kinase and insulin receptor signaling pathways, relative to swimmers. The genes encoding activity-related cytoskeletal protein (Arc) and brain-derived neurotrophic factor (BDNF) were upregulated in proficient learners, relative to swimmers and home cage controls, while the gene encoding Rho GTPase activating protein 32 (GRIT) was downregulated. We explored the regulation of Arc, BDNF, and GRIT expression in greater morphological detail using in situ hybridization. Recall during probe trials enhanced Arc expression across multiple cortical regions involved in the cognitive component of water maze learning, while BDNF expression was more homogeneously upregulated across cortical regions involved in the associational and sensorimotor aspects of water maze training. In contrast, levels of GRIT expression were uniformly reduced across all cortical regions examined.
These results suggest that cortical gene transcription is responsive to learning in aged mice that exhibit behavioral proficiency, and support a distributed hypothesis of memory storage across multiple cortical compartments.
BMC Neuroscience 06/2011; 12:63. · 3.04 Impact Factor
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ABSTRACT: We have created a novel enzyme reactor using electric field-mediated orientation and immobilization of proteolytic enzymes (trypsin/chymotrypsin) on biocompatible PVDF membranes in a continuous flow-through chamber. Using less than 5min, this reactor in various enzyme combinations can produce enhanced rapid digestion for standardized prototypic proteins, hydrophilic proteins and hydrophobic transmembrane proteins when compared to in-solution techniques. With improved digestive efficiency, our reactor improved the overall functional analysis of lipid raft proteomes by identifying more closely functionally linked proteins and elucidated a richer set of biological processes and pathways linked to the proteins than traditional in-solution methods.
Journal of proteomics 02/2011; 74(7):1030-5. · 5.07 Impact Factor
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Wayne Chadwick,
John P Boyle,
Yu Zhou,
Liyun Wang,
Sung-Soo Park,
Bronwen Martin,
Rui Wang,
Kevin G Becker,
William H Wood,
Yongqing Zhang,
Chris Peers,
Stuart Maudsley
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ABSTRACT: The central nervous system normally functions at O(2) levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O(2)-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O(2) tensions compared to the cell culture standard of 20% O(2), to investigate their ability to sense and translate this O(2) information to transcriptional activity. Variance of ambient O(2) tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O(2) tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O(2) tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O(2) tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional 'programs' may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.
PLoS ONE 01/2011; 6(6):e21638. · 4.09 Impact Factor
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Wayne Chadwick,
Nick Mitchell,
Jenna Caroll,
Yu Zhou,
Sung-Soo Park,
Liyun Wang,
Kevin G Becker,
Yongqing Zhang,
Elin Lehrmann,
William H Wood,
Bronwen Martin,
Stuart Maudsley
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ABSTRACT: Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
PLoS ONE 01/2011; 6(6):e21660. · 4.09 Impact Factor
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ABSTRACT: Oxidative stressors such as hydrogen peroxide control the activation of many interconnected signaling systems and are implicated in neurodegenerative disease etiology. Application of hydrogen peroxide to PC12 cells activated multiple tyrosine kinases (c-Src, epidermal growth factor receptor (EGFR), and Pyk2) and the serine-threonine kinase ERK1/2. Peroxide-induced ERK1/2 activation was sensitive to intracellular calcium chelation and EGFR and c-Src kinase inhibition. Acute application and removal of peroxide allowed ERK1/2 activity levels to rapidly subside to basal serum-deprived levels. Using this protocol, we demonstrated that ERK1/2 activation tachyphylaxis developed upon repeated peroxide exposures. This tachyphylaxis was independent of c-Src/Pyk2 tyrosine phosphorylation but was associated with a progressive reduction of peroxide-induced EGFR tyrosine phosphorylation, EGFR interaction with growth factor receptor binding protein 2, and a redistribution of EGFR from the plasma membrane to the cytoplasm. Our data indicates that components of peroxide-induced ERK1/2 cascades are differentially affected by repeated exposures, indicating that oxidative signaling may be contextually variable.
Journal of signal transduction. 01/2011; 2011:636951.
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ABSTRACT: The growth and development in the last decade of accurate and reliable mass data collection techniques has greatly enhanced our comprehension of cell signaling networks and pathways. At the same time however, these technological advances have also increased the difficulty of satisfactorily analyzing and interpreting these ever-expanding datasets. At the present time, multiple diverse scientific communities including molecular biological, genetic, proteomic, bioinformatic, and cell biological, are converging upon a common endpoint, that is, the measurement, interpretation, and potential prediction of signal transduction cascade activity from mass datasets. Our ever increasing appreciation of the complexity of cellular or receptor signaling output and the structural coordination of intracellular signaling cascades has to some extent necessitated the generation of a new branch of informatics that more closely associates functional signaling effects to biological actions and even whole-animal phenotypes. The ability to untangle and hopefully generate theoretical models of signal transduction information flow from transmembrane receptor systems to physiological and pharmacological actions may be one of the greatest advances in cell signaling science. In this overview, we shall attempt to assist the navigation into this new field of cell signaling and highlight several methodologies and technologies to appreciate this exciting new age of signal transduction.
Methods in molecular biology (Clifton, N.J.) 01/2011; 756:99-130.
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ABSTRACT: Receptors for hormones of the hypothalamic-pituitary-gonadal axis are expressed throughout the brain. Age-related decline in gonadal reproductive hormones cause imbalances of this axis and many hormones in this axis have been functionally linked to neurodegenerative pathophysiology. Gonadotropin-releasing hormone (GnRH) plays a vital role in both central and peripheral reproductive regulation. GnRH has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in GnRH actions at non-pituitary peripheral targets. GnRH ligands and receptors are found throughout the brain where they may act to control multiple higher functions such as learning and memory function and feeding behavior. The actions of GnRH in mammals are mediated by the activation of a unique rhodopsin-like G protein-coupled receptor that does not possess a cytoplasmic carboxyl terminal sequence. Activation of this receptor appears to mediate a wide variety of signaling mechanisms that show diversity in different tissues. Epidemiological support for a role of GnRH in central functions is evidenced by a reduction in neurodegenerative disease after GnRH agonist therapy. It has previously been considered that these effects were not via direct GnRH action in the brain, however recent data has pointed to a direct central action of these ligands outside the pituitary. We have therefore summarized the evidence supporting a central direct role of GnRH ligands and receptors in controlling central nervous physiology and pathophysiology.
CNS & neurological disorders drug targets 11/2010; 9(5):651-60. · 3.57 Impact Factor
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ABSTRACT: Our understanding of the complex signaling neurophysiology of the central nervous system has facilitated the exploration of potential novel receptor-ligand system targets for disorders of this most complex organ. In recent years, many relatively neglected receptor-ligand systems have been re-evaluated with respect to their ability to potently modulate discrete tracts in the central nervous system. One such system is the tachykinin (previously neurokinin) system. The multiple heptahelical G protein-coupled receptors and neuropeptide ligands that comprise this system may be significantly involved in more central nervous systems actions than previously thought, including sleep disorders, amyotrophic lateral sclerosis, Alzheimer's disease and Machado-Joseph disease. The development of our understanding of the role of the tachykinin receptor-ligand system in higher order central functions is likely to allow the creation of more specific and selective tachykinin-related neurotherapeutics.
CNS & neurological disorders drug targets 11/2010; 9(5):627-35. · 3.57 Impact Factor
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Bronwen Martin,
Yu-Kyong Shin,
Caitlin M White,
Sunggoan Ji,
Wook Kim,
Olga D Carlson,
Joshua K Napora, Wayne Chadwick,
Megan Chapter,
James A Waschek,
Mark P Mattson,
Stuart Maudsley,
Josephine M Egan
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ABSTRACT: It is becoming apparent that there is a strong link between taste perception and energy homeostasis. Recent evidence implicates gut-related hormones in taste perception, including glucagon-like peptide 1 and vasoactive intestinal peptide (VIP). We used VIP knockout mice to investigate VIP's specific role in taste perception and connection to energy regulation.
Body weight, food intake, and plasma levels of multiple energy-regulating hormones were measured and pancreatic morphology was determined. In addition, the immunocytochemical profile of taste cells and gustatory behavior were examined in wild-type and VIP knockout mice.
VIP knockout mice demonstrate elevated plasma glucose, insulin, and leptin levels, with no islet beta-cell number/topography alteration. VIP and its receptors (VPAC1, VPAC2) were identified in type II taste cells of the taste bud, and VIP knockout mice exhibit enhanced taste preference to sweet tastants. VIP knockout mouse taste cells show a significant decrease in leptin receptor expression and elevated expression of glucagon-like peptide 1, which may explain sweet taste preference of VIP knockout mice.
This study suggests that the tongue can play a direct role in modulating energy intake to correct peripheral glycemic imbalances. In this way, we could view the tongue as a sensory mechanism that is bidirectionally regulated and thus forms a bridge between available foodstuffs and the intricate hormonal balance in the animal itself.
Diabetes 02/2010; 59(5):1143-52. · 8.29 Impact Factor
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ABSTRACT: Various animal models of Alzheimer's disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins. We have used mass analytical techniques and multiple bioinformatic approaches to better appreciate the intricate interactions of these multifunctional proteins in the 3xTgAD murine model of AD. Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice.
International journal of Alzheimer's disease. 01/2010; 2010:604792.
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ABSTRACT: Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations.
PLoS ONE 01/2010; 5(12):e14352. · 4.09 Impact Factor
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ABSTRACT: Through evolutionary history the primary mechanism by which the cells or tissues of most organisms sense their environment
has been the heptahelical G protein–coupled receptor (GPCR). This prototypic receptive entity has its origins in the earliest
forms of life and often comprises up to 5% of the genome of most unicellular and multicellular life forms. The GPCR system
has adapted to perceive almost all forms of environmental entities, for example, photons, odorants, lipids, carbohydrates,
peptides, and nucleic acids. The GPCR system has also likely adapted to the presence of exogenous compounds that may at some
doses be deleterious but at lower levels may indeed possess beneficial actions. Therefore, with respect to the evolutionary
pressure of diverse environments, it would be an extreme advantage for an organism to adapt multiple components of its primary
receptive system to take advantage of any beneficial effects of agents present in harsh or damaging environments.
KeywordsGprotein–coupled receptor-Dose response-Allosteric-Conformation-Environment-Flavor-Receptive
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