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Alzheimer's
Terms modified by Alzheimer's Selected AbstractsParallel protein folding with STAPLCONCURRENCY AND COMPUTATION: PRACTICE & EXPERIENCE, Issue 14 2005Shawna Thomas Abstract The protein-folding problem is a study of how a protein dynamically folds to its so-called native state,an energetically stable, three-dimensional conformation. Understanding this process is of great practical importance since some devastating diseases such as Alzheimer's and bovine spongiform encephalopathy (Mad Cow) are associated with the misfolding of proteins. We have developed a new computational technique for studying protein folding that is based on probabilistic roadmap methods for motion planning. Our technique yields an approximate map of a protein's potential energy landscape that contains thousands of feasible folding pathways. We have validated our method against known experimental results. Other simulation techniques, such as molecular dynamics or Monte Carlo methods, require many orders of magnitude more time to produce a single, partial trajectory. In this paper we report on our experiences parallelizing our method using STAPL (Standard Template Adaptive Parallel Library) that is being developed in the Parasol Lab at Texas A&M. An efficient parallel version will enable us to study larger proteins with increased accuracy. We demonstrate how STAPL enables portable efficiency across multiple platforms, ranging from small Linux clusters to massively parallel machines such as IBM's BlueGene/L, without user code modification. Copyright © 2005 John Wiley & Sons, Ltd. [source] Variable-field relaxometry of iron-containing human tissues: a preliminary studyCONTRAST MEDIA & MOLECULAR IMAGING, Issue 4 2009Aline Hocq Abstract Excess iron is found in brain nuclei from neurodegenerative patients (with Parkinson's, Alzheimer's and Huntington's diseases) and also in the liver and spleen of cirrhosis, hemochromatosis and thalassaemia patients. Ferritin, the iron-storing protein of mammals, is known to darken T2 -weighted MR images. Understanding NMR tissue behavior may make it possible to detect those diseases, to follow their evolution and finally to establish a protocol for non-invasive measurement of an organ's iron content using MRI methods. In this preliminary work, the MR relaxation properties of embalmed iron-containing tissues were studied as well as their potential correlation with the iron content of these tissues. Relaxometric measurements (T1 and T2) of embalmed samples of brain nuclei (caudate nucleus, dentate nucleus, globus pallidus, putamen, red nucleus and substantia nigra), liver and spleen from six donors were made at different magnetic fields (0.00023,14 T). The influence of the inter-echo time on transverse relaxation was also studied. Moreover, iron content of tissues was determined by inductively coupled plasma atomic emission spectroscopy. In brain nuclei, 1/T2 increases quadratically with the field and depends on the inter-echo time in CPMG sequences at high fields, both features compatible with an outer sphere relaxation theory. In liver and spleen, 1/T2 increases linearly with the field and depends on the inter-echo time at all fields. In our study, a correlation between 1/T2 and iron concentration is observed. Explaining the relaxation mechanism for these tissues is likely to require a combination of several models. The value of 1/T2 at high field could be used to evaluate iron accumulation in vivo. In the future, confirmation of those features is expected to be achieved from measurements of fresh (not embalmed) human tissues. Copyright © 2009 John Wiley & Sons, Ltd. [source] Progress in the development of new treatments for combined Alzheimer's and Parkinson's diseasesDRUG DEVELOPMENT RESEARCH, Issue 3 2002Eliezer Masliah Abstract Misfolding of synaptic molecules such as amyloid , peptide and ,-synuclein has been proposed to play a key role in the mechanisms of neurodegeneration in Alzheimer's and Parkinson's disease, respectively. Notably, the majority of patients with Alzheimer's disease also have ,-synuclein-immunoreactive Lewy bodies, and a substantial proportion of them develop a form of parkinsonism also known as Lewy body disease, that defies conventional therapies. Thus, factors involved in the pathogenesis of Alzheimer's disease might promote the development of particularly recalcitrant forms of Lewy body disease. We have shown that the amyloid , peptide 1-42, of Alzheimer's disease, promotes the toxic conversion of ,-synuclein and accelerates ,-synuclein-dependent deficits in transgenic mice. Understanding the mechanisms promoting the toxic conversion of ,-synuclein is of critical importance for the design of rationale treatments for Lewy body disease and transgenic models hold the promise for the development of such novel therapies. In this context therapies aimed at: (1) reducing amyloid , peptide 1-42 production, (2) blocking toxic ,-synuclein oligomerization (e.g., ,-synuclein, antioxidants), (3) promoting ,-synuclein protofibril degradation, and (4) protecting neurons (e.g., anti-oxidants, neurotrophic agents) against toxic ,-synuclein aggregates might prove to be significantly useful in the treatment of Lewy body disease. We characterized ,-synuclein, the non-amyloidogenic homologue of ,-synuclein, as an inhibitor of aggregation of ,-synuclein. Our results raise the intriguing possibility that ,-synuclein might be a natural negative regulator of ,-synuclein aggregation, and that a similar class of endogenous factors might modulate the toxic conversion of other molecules involved in neurodegeneration. Such an anti-amyloidogenic property of ,-synuclein in combination with other treatments might also provide a novel strategy for the treatment of neurodegenerative disorders. Drug Dev. Res. 56:282,292, 2002. © 2002 Wiley-Liss, Inc. [source] Mapping the Progress of Alzheimer's and Parkinson's DiseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2003K. A. Jellinger No abstract is available for this article. [source] Glutathione depletion in hippocampal cells increases levels of H and L ferritin and glutathione S-transferase mRNAsGENES TO CELLS, Issue 5 2007Nadya Morozova Glutathione plays an essential role in maintaining cellular redox balance, protecting cells from oxidative stress and detoxifying xenobiotic compounds. Glutathione depletion has been implicated in neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Cells of neuronal origin are acutely sensitive to glutathione depletion, providing an avenue for studying the mechanisms invoked for neuronal survival in response to oxidant challenge. We investigated the changes in mRNA profile in HT22 hippocampal cells following administration of homocysteic acid (HCA), a glutathione-depleting drug. We report that HCA treatment of HT22 murine hippocampal cells increases the levels of the mRNAs encoding at least three proteins involved in protection from oxidant injury, the mRNAs encoding heavy (H) and light (L) ferritin and glutathione S-transferase (GST). [source] Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layersHIPPOCAMPUS, Issue 8 2010Chris M. Valdez Abstract Changes in brain cholesterol homeostasis are associated with multiple diseases, such as Alzheimer's and Huntington's; however, controversy persists as to whether adult neurons produce their own cholesterol, or if it is outsourced to astrocytes. To address this issue, we analyzed 25 genes most immediately involved in cholesterol homeostasis from in situ data provided by the Allen Brain Mouse Atlas. We compared the relative mRNA expression in the pyramidal and granule layers, populated with neurons, with the rest of the hippocampus which is populated with neuronal processes and glia. Comparing the expression of the individual genes to markers for neurons and astrocytes, we found that cholesterol homeostasis genes are preferentially targeted to neuronal layers. Therefore, changes in gene expression levels might affect neuronal populations directly. © 2010 Wiley-Liss, Inc. [source] Quantitative evaluation of automated skull-stripping methods applied to contemporary and legacy images: Effects of diagnosis, bias correction, and slice locationHUMAN BRAIN MAPPING, Issue 2 2006Christine Fennema-Notestine Abstract Performance of automated methods to isolate brain from nonbrain tissues in magnetic resonance (MR) structural images may be influenced by MR signal inhomogeneities, type of MR image set, regional anatomy, and age and diagnosis of subjects studied. The present study compared the performance of four methods: Brain Extraction Tool (BET; Smith [2002]: Hum Brain Mapp 17:143,155); 3dIntracranial (Ward [1999] Milwaukee: Biophysics Research Institute, Medical College of Wisconsin; in AFNI); a Hybrid Watershed algorithm (HWA, Segonne et al. [2004] Neuroimage 22:1060,1075; in FreeSurfer); and Brain Surface Extractor (BSE, Sandor and Leahy [1997] IEEE Trans Med Imag 16:41,54; Shattuck et al. [2001] Neuroimage 13:856,876) to manually stripped images. The methods were applied to uncorrected and bias-corrected datasets; Legacy and Contemporary T1 -weighted image sets; and four diagnostic groups (depressed, Alzheimer's, young and elderly control). To provide a criterion for outcome assessment, two experts manually stripped six sagittal sections for each dataset in locations where brain and nonbrain tissue are difficult to distinguish. Methods were compared on Jaccard similarity coefficients, Hausdorff distances, and an Expectation-Maximization algorithm. Methods tended to perform better on contemporary datasets; bias correction did not significantly improve method performance. Mesial sections were most difficult for all methods. Although AD image sets were most difficult to strip, HWA and BSE were more robust across diagnostic groups compared with 3dIntracranial and BET. With respect to specificity, BSE tended to perform best across all groups, whereas HWA was more sensitive than other methods. The results of this study may direct users towards a method appropriate to their T1 -weighted datasets and improve the efficiency of processing for large, multisite neuroimaging studies. Hum. Brain Mapping, 2005. © 2005 Wiley-Liss, Inc. [source] Cognitive leisure activities and their role in preventing dementia: a systematic reviewINTERNATIONAL JOURNAL OF EVIDENCE BASED HEALTHCARE, Issue 1 2010Cindy Stern BHSc(Hons) Abstract Background, Dementia inflicts a tremendous burden on the healthcare system. Identifying protective factors or effective prevention strategies may lead to considerable benefits. One possible strategy mentioned in the literature relates to participation in cognitive leisure activities. Aim, To determine the effectiveness of cognitive leisure activities in preventing Alzheimer's and other dementias among older adults. Inclusion criteria Types of participants.,Adults aged at least 60 years of age with or without a clinical diagnosis of dementia that resided in the community or care setting. Types of interventions.,Cognitive leisure activities, defined as activities that required a mental response from the individual taking part in the activity (e.g. reading). Types of outcomes.,The presence or absence of dementia was the outcome of interest. Types of studies.,Any randomised controlled trials, other experimental studies, as well as cohort, case,control and cross-sectional studies were considered for inclusion. Search strategy.,A search for published and unpublished studies in the English language was undertaken with no publication date restriction. Methodological quality, Each study was appraised independently by two reviewers using the standard Joanna Briggs Institute instruments. Data collection and analysis, Information was extracted from studies meeting quality criteria using the standard Joanna Briggs Institute tools. Because of the heterogeneity of populations and interventions, meta-analyses were not possible and results are presented in narrative form. Results, There were no randomised controlled trials located that met inclusion criteria. Thirteen observational studies were included in the review; the majority were cohort design. Because of the heterogeneity of interventions, the study design, the way in which they were grouped and the different stages of life they were measured at, statistical pooling was not appropriate. Studies were grouped by stage of adult life participation when interventions were undertaken, that is, early adulthood, middle adulthood and late life. Five out of six studies showed a positive association between participating in activities and a reduced risk of developing Alzheimer's disease and other dementias when interventions were undertaken in middle adulthood and six out of seven studies produced a positive association for late life participation. Results indicated that some activities might be more beneficial than others; however, results should be interpreted with caution because of the subjective nature of activity inclusion. Conclusion ,,Actively participating in cognitive leisure activities during mid- or late life may be beneficial in preventing the risk of Alzheimer's disease and other dementias in the elderly; however, the evidence is currently not strong enough to infer a direct causal relationship. ,,Participating in selected cognitive leisure activities may be more favourable than others but currently there is no strong evidence to recommend one over the other. [source] Differences in depression symptoms in patients with Alzheimer's and Parkinson's diseases: evidence from the 15-item Geriatric Depression Scale (GDS-15)INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 10 2007Daniel Weintraub Abstract Objective Depression occurs frequently in patients with both Alzheimer's disease (AD) and Parkinson's disease (PD), but there has been little comparison of depression symptoms in the two populations. Method The 15-item Geriatric Depression Scale (GDS-15) was administered as a depression screening instrument to 232,AD patients and 266,PD specialty care patients with at most mild dementia. Logistic regression models were used to determine disease-specific associations with individual GDS-15 items, and factor analysis was used to assess GDS-15 factor structure in the two populations. Results Controlling for total GDS-15 score and other covariates, AD patients reported more dissatisfaction with life (p,=,0.03) and memory problems (p,<,0.001), while PD patients reported more fearfulness (p,=,0.01), helplessness (p,<,0.01), a preference to stay at home (p,=,0.02), and diminished energy (p,<,0.01). Three factors were generated in PD (explaining 55% of the total variance) and five in AD (explaining 59% of the total variance), and the two main factors generated in both populations related primarily to unhappiness and negative thoughts. Conclusions The factor structure of the GDS-15 is similar in AD and PD patients with at most mild stage dementia, but between-group differences on 6 of the GDS-15 items suggests the non-specificity of certain items in the two populations. Copyright © 2007 John Wiley & Sons, Ltd. [source] Factor structure of the Cornell Scale for Depression in Dementia among Japanese poststroke patientsINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 8 2002Andrea S. Schreiner Abstract Background The present study reports on the first translation and use of the Cornell Scale for Depression in Dementia (CSDD) (Alexopoulos, Abrams, Young, & Shamoian, 1988) among poststroke patients (n,=,101) in Japan. Objectives The study had three main purposes: 1. To examine the factor structure of the CSDD among Japanese poststroke patients; 2. To compare this with the factor structure identified for Anglo-American Alzheimer's (AD) patients; and 3. To examine the prevalence and covariates of depressive symptoms among the Japanese stroke survivors. Methods Poststroke patients and their caregivers (n,=,202), at a random sample of neurological hospitals in western Japan, were interviewed using the study instruments. Data was also collected from patient charts. All subjects at each site who met the study criteria participated in the study. Results The four-factor solution for poststroke subjects was analogous to that found among AD patients with 2 main exceptions. In contrast to AD patients: 1. Physical complaints were unrelated to depressed mood in stroke patients; and 2. Agitation and psychosis loaded with depressed mood in stroke patients rather than as a separate unique factor as in AD patients. However, in the exploratory 5-factor model, agitation and suicidal ideation comprised a unique factor. Using standard cutoff scores for the CSDD, 58.2% of poststroke patients had scores suggesting possible depression. CSDD scores were not related to functional ability, or stroke characteristics such as aphasia or right or left-sided paralysis. However, scores were significantly higher among subjects,2 years poststroke. Feelings of irritability, anxiety, sadness, and sleep problems were most prevalent. Discussion Despite the prevalence of depressive symptoms, none of the subjects were currently receiving any mental health treatment. Findings suggest that symptoms differ by poststroke duration, which may necessitate different treatment approaches. Copyright © 2002 John Wiley & Sons, Ltd. [source] Unraveling the mysteries of protein folding and misfoldingIUBMB LIFE, Issue 12 2008Heath Ecroyd Abstract This mini-review focuses on the processes and consequences of protein folding and misfolding. The latter process often leads to protein aggregation and precipitation with the aggregates adopting either highly ordered (amyloid fibril) or disordered (amorphous) forms. In particular, the amyloid fibril is discussed because this form has gained considerable notoriety due to its close links to a variety of debilitating diseases including Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob diseases, and type-II diabetes. In each of these diseases a different protein forms fibrils, yet the fibrils formed have a very similar structure. The mechanism by which fibrils form, fibril structure, and the cytotoxicity associated with fibril formation are discussed. The generic nature of amyloid fibril structure suggests that a common target may be accessible to treat amyloid fibril-associated diseases. As such, the ability of some molecules, for example, the small heat-shock family of molecular chaperone proteins, to inhibit fibril formation is of interest due to their therapeutic potential. © 2008 IUBMB IUBMB Life, 60(12): 769,774, 2008 [source] Artificial hydration and nutrition in advanced Alzheimer's disease: facilitating family decision-makingJOURNAL OF CLINICAL NURSING, Issue 6 2004Sandra K Eggenberger PhD Background., As Alzheimer's disease progresses to its final stages of dementia and dysphagia, whereby patients can no longer swallow food and fluids, families suffer with difficult decisions regarding initiation of artificial hydration and nutrition. Aims and objectives., Through the use of a hypothetical family scenario, this theoretical article presents the ethical principals of beneficence and autonomy as a framework for use by nurses to hear and inform family decision-makers of the physiology of death in the advanced stages of Alzheimer's and examines the current literature related to benefits and burdens of artificial hydration and nutrition. Conclusions., While a beneficial consideration, ethical principles are critiqued for their inability to provide an absolute answer and relieve family suffering in this clinical situation. Relevance to clinical practice., A nurse-lead consensus building process is proposed to guide family decision-making regarding artificial hydration and nutrition with advanced Alzheimer's disease. [source] Smoking can be good for youJOURNAL OF COSMETIC DERMATOLOGY, Issue 2 2004R Wolf Summary Smoking is without doubt one of the greatest causes of avoidable illness and death in the modern world. Most well known is the relationship between smoking and numerous cancers, cerebrovascular and cardiovascular disease. Smoking and most especially nicotine, are, however, sometimes beneficial in certain diseases, including Parkinson's, Alzheimer's, allergic alveolitis, nausea and vomiting of pregnancy, pre-eclampsia, fibroids, carcinoma of body of uterus, ulcerative colitis, pyoderma gangrenosum, aphthous stomatitis and ulceration, pemphigus, herpes simplex and acne. In the immensely justifiable enthusiasm to discredit this dangerous activity, the mechanisms behind these beneficial effects tend to have been un-discussed or ignored. It is the aim of this paper to spur interest in the reasons for these effects. If the mechanisms are elucidated, therapeutic advances may be possible. [source] Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protectionAGING CELL, Issue 2 2010Ehud Cohen Summary Toxic protein aggregation (proteotoxicity) is a unifying feature in the development of late-onset human neurodegenerative disorders. Reduction of insulin/IGF-1 signaling (IIS), a prominent lifespan, developmental and reproductive regulatory pathway, protects worms from proteotoxicity associated with the aggregation of the Alzheimer's disease-linked A, peptide. We utilized transgenic nematodes that express human A, and found that late life IIS reduction efficiently protects from A, toxicity without affecting development, reproduction or lifespan. To alleviate proteotoxic stress in the animal, the IIS requires heat shock factor (HSF)-1 to modulate a protein disaggregase, while DAF-16 regulates a presumptive active aggregase, raising the question of how these opposing activities could be co-regulated. One possibility is that HSF-1 and DAF-16 have distinct temporal requirements for protection from proteotoxicity. Using a conditional RNAi approach, we found an early requirement for HSF-1 that is distinct from the adult functions of DAF-16 for protection from proteotoxicity. Our data also indicate that late life IIS reduction can protect from proteotoxicity when it can no longer promote longevity, strengthening the prospect that IIS reduction might be a promising strategy for the treatment of neurodegenerative disorders caused by proteotoxicity. [source] Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acidJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Fiona E. Harrison Abstract Oxidative stress is implicated in the cognitive deterioration associated with normal aging as well as neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We investigated the effect of ascorbic acid (vitamin C) on oxidative stress, cognition, and motor abilities in mice null for gulono-,-lactone oxidase (Gulo). Gulo,/, mice are unable to synthesize ascorbic acid and depend on dietary ascorbic acid for survival. Gulo,/, mice were given supplements that provided them either with ascorbic acid levels equal to- or slightly higher than wild-type mice (Gulo-sufficient), or lower than physiological levels (Gulo-low) that were just enough to prevent scurvy. Ascorbic acid is a major anti-oxidant in mice and any reduction in ascorbic acid level is therefore likely to result in increased oxidative stress. Ascorbic acid levels in the brain and liver were higher in Gulo-sufficient mice than in Gulo-low mice. F4 -neuroprostanes were elevated in cortex and cerebellum in Gulo-low mice and in the cortex of Gulo-sufficient mice. All Gulo,/, mice were cognitively normal but had a strength and agility deficit that was worse in Gulo-low mice. This suggests that low levels of ascorbic acid and elevated oxidative stress as measured by F4 -neuroprostanes alone are insufficient to impair memory in the knockouts but may be responsible for the exacerbated motor deficits in Gulo-low mice, and ascorbic acid may have a vital role in maintaining motor abilities. [source] PPAR: a therapeutic target in Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Rajnish K. Chaturvedi Abstract Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD. [source] BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulationJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Yinghui Hu Abstract It is clear that brain-derived neurotrophic factor (BDNF) plays a crucial role in organizing the response of the genome to dynamic changes in the extracellular environment that enable brain plasticity. BDNF has emerged as one of the most important signaling molecules for the developing nervous system as well as the impaired nervous system, and multiple diseases, such as Alzheimer's, Parkinson's, Huntington's, epilepsy, Rett's syndrome, and psychiatric depression, are linked by their association with potential dysregulation of BDNF-driven signal transduction programs. These programs are responsible for controlling the amount of activated transcription factors, such as cAMP response element binding protein, that coordinate the expression of multiple brain proteins, like ion channels and early growth response factors, whose job is to maintain the balance of excitation and inhibition in the nervous system. In this review, we will explore the evidence for BDNF's role in gene regulation side by side with its potential role in the etiology of neurological diseases. It is hoped that by bringing the datasets together in these diverse fields we can help develop the foundation for future studies aimed at understanding basic principles of gene regulation in the nervous system and how they can be harnessed to develop new therapeutic opportunities. [source] Poster Session PSM02: Alzheimer's and agingJOURNAL OF NEUROCHEMISTRY, Issue 2005Article first published online: 15 JUL 200 First page of article [source] Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity: functional potentiation by isomerization and dimerizationJOURNAL OF NEUROCHEMISTRY, Issue 6 2003Kenzo Terashita Abstract The 24-residue peptide Humanin (HN), containing two Ser residues at positions 7 and 14, protects neuronal cells from insults of various Alzheimer's disease (AD) genes and A,. It was not known why the rescue function of (S14G)HN is more potent than HN by two to three orders of magnitude. Investigating the possibility that the post-translational modification of Ser14 might play a role, we found that HN with d -Ser at position 14 exerts neuroprotection more potently than HN by two to three orders of magnitude, whereas d -Ser7 substitution does not affect the rescue function of HN. On the other hand, S7A substitution nullified the HN function. Multiple series of experiments indicated that Ser7 is necessary for self-dimerization of HN, which is essential for neuroprotection by this factor. These findings indicate that the rescue function of HN is quantitatively modulated by d -isomerization of Ser14 and Ser7-relevant dimerization, allowing for the construction of a very potent HN derivative that was fully neuroprotective at 10 pm against 25 µm A,1,43. This study provides important clues to the understanding of the neuroprotective mechanism of HN, as well as to the development of novel AD therapeutics. [source] Thermodynamic and kinetic origins of Alzheimer's and related diseases: A chemical engineer's perspective ,AICHE JOURNAL, Issue 8 2008Carol K. Hall First page of article [source] Endoplasmic reticulum dysfunction , a common denominator for cell injury in acute and degenerative diseases of the brain?JOURNAL OF NEUROCHEMISTRY, Issue 4 2001Wulf Paschen Various physiological, biochemical and molecular biological disturbances have been put forward as mediators of neuronal cell injury in acute and chronic pathological states of the brain such as ischemia, epileptic seizures and Alzheimer's or Parkinson's disease. These include over-activation of glutamate receptors, a rise in cytoplasmic calcium activity and mitochondrial dysfunction. The possible involvement of the endoplasmic reticulum (ER) dysfunction in this process has been largely neglected until recently, although the ER plays a central role in important cell functions. Not only is the ER involved in the control of cellular calcium homeostasis, it is also the subcellular compartment in which the folding and processing of membrane and secretory proteins takes place. The fact that blocking of these processes is sufficient to cause cell damage indicates that they are crucial for normal cell functioning. This review presents evidence that ER function is disturbed in many acute and chronic diseases of the brain. The complex processes taken place in this subcellular compartment are however, affected in different ways in various disorders; whereas the ER-associated degradation of misfolded proteins is affected in Parkinson's disease, it is the unfolded protein response which is down-regulated in Alzheimer's disease and the ER calcium homeostasis that is disturbed in ischemia. Studying the consequences of the observed deteriorations of ER function and identifying the mechanisms causing ER dysfunction in these pathological states of the brain will help to elucidate whether neurodegeneration is indeed caused by these disturbances, and will help to fascilitate the search for drugs capable of blocking the pathological process directly at an early stage. [source] Multiple mechanisms that prevent excessive brain inflammationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2007Myung-Soon Yang Abstract Inflammation of the injured brain has a double-edged effect. Inflammation protects the brain from infection, but it aggravates injury. Furthermore, brain inflammation is considered a risk factor for neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Emerging evidence supports the activation of negative regulatory mechanisms during this process to prevent prolonged and extensive inflammation. The inflammatory stimulators themselves or products of inflammatory cells may induce the expression of negative feedback regulators, such as suppressor of cytokine signaling (SOCS)-family proteins, antioxidant enzymes, and antiinflammatory cytokines. Furthermore, death of activated microglia (major inflammatory cells in the brain) may regulate brain inflammation. Astrocytes, the most abundant cells in the brain, may also act in preventing microglial overactivation. Therefore, we propose that the extent and duration of brain inflammation is tightly regulated through the cooperation of multiple mechanisms to maximize antipathogenic effects and minimize tissue damage. © 2007 Wiley-Liss, Inc. [source] Dental Amalgam and Multiple Sclerosis: A Systematic Review and Meta-AnalysisJOURNAL OF PUBLIC HEALTH DENTISTRY, Issue 1 2007Kevin K. Aminzadeh Bsc Pharm Abstract Objectives: Amalgam restorations have long been controversial due to their mercury content. Allegations that the mercury may be linked to nervous disorders such as Alzheimer's, chronic fatigue syndrome, and multiple sclerosis (MS) have fueled the calls for the removal of amalgam restorations from dentists' armamentarium. To explore and quantify the association between amalgam restorations and MS we have conducted a systematic review and meta-analysis of the literature. Methods: A systematic search in Medline (from 1966 to April 2006), EMBASE (2006, Week 16), and the Cochrane library (Issue 2, 2006) for English-language articles meeting specific definitions of MS and amalgam exposure was conducted. Studies were also identified using the references of retrieved articles. Studies were independently reviewed by two authors and disagreements were resolved by consensus. Studies were selected based on an a priori of defined criteria. Odds ratios (ORs) or relative risks were pooled using the random effects model. Heterogeneity was assessed using Q statistics. Results: The pooled OR for the risk of MS among amalgam users was consistent, with a slight, nonstatistically significant increase between amalgam use and risk of MS. Conclusion: Future studies that take into consideration the amalgam restoration size and surface area along with the duration of exposure are needed in order to definitively rule out any link between amalgam and MS. [source] Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic StudiesALCOHOLISM, Issue 2 2009Michael A. Collins In contrast to many years of important research and clinical attention to the pathological effects of alcohol (ethanol) abuse, the past several decades have seen the publication of a number of peer-reviewed studies indicating the beneficial effects of light-moderate, nonbinge consumption of varied alcoholic beverages, as well as experimental demonstrations that moderate alcohol exposure can initiate typically cytoprotective mechanisms. A considerable body of epidemiology associates moderate alcohol consumption with significantly reduced risks of coronary heart disease and, albeit currently a less robust relationship, cerebrovascular (ischemic) stroke. Experimental studies with experimental rodent models and cultures (cardiac myocytes, endothelial cells) indicate that moderate alcohol exposure can promote anti-inflammatory processes involving adenosine receptors, protein kinase C (PKC), nitric oxide synthase, heat shock proteins, and others which could underlie cardioprotection. Also, brain functional comparisons between older moderate alcohol consumers and nondrinkers have received more recent epidemiological study. In over half of nearly 45 reports since the early 1990s, significantly reduced risks of cognitive loss or dementia in moderate, nonbinge consumers of alcohol (wine, beer, liquor) have been observed, whereas increased risk has been seen only in a few studies. Physiological explanations for the apparent CNS benefits of moderate consumption have invoked alcohol's cardiovascular and/or hematological effects, but there is also experimental evidence that moderate alcohol levels can exert direct "neuroprotective" actions,pertinent are several studies in vivo and rat brain organotypic cultures, in which antecedent or preconditioning exposure to moderate alcohol neuroprotects against ischemia, endotoxin, ,-amyloid, a toxic protein intimately associated with Alzheimer's, or gp120, the neuroinflammatory HIV-1 envelope protein. The alcohol-dependent neuroprotected state appears linked to activation of signal transduction processes potentially involving reactive oxygen species, several key protein kinases, and increased heat shock proteins. Thus to a certain extent, moderate alcohol exposure appears to trigger analogous mild stress-associated, anti-inflammatory mechanisms in the heart, vasculature, and brain that tend to promote cellular survival pathways. [source] Expression Of O-Acetyl Sialic Acid On Cerebral Microcirculation In A Glycine Or Taurine Treated Diabetic Rat ModelJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000A Noe Expression of sialic acid is altered in Diabetes mellitus. This modification has also been involved with both vascular and neurologic diseases, and with the increase of no enzymatic glycosylation of proteins. In our opinion, the lectins were very useful with specificity for sialic acids in order to determine the level of sialic acid expression on cerebral microcirculation in a diabetic Wistar rat model with streptozotocin. In this model, the glycine (1%) and taurine (0.5%) aminoacids were placed in drinking-water by six months. At the end of this time, the animals were sacrificed, their brains surgically removed and frozen in liquid nitrogen, and the specimens cut in serial sections. Immediately, the sections were incubated with different biotin-labelled lectins specific to sialic acid using peroxidase-labelled avidin as second ligand and H2O2 chromogen. The results showed greater O-acetyl sialic acid expression in cerebral capillaries of untreated diabetic rats than in glycine-, taurine-treated diabetic rats or than in control animals. The minor sialic acid expression may be an indicator of degenerative diseases such as Alzheimer's or the vascular disease of diabetic patients and probably is related to cellular protective properties of the glycine and taurine aminoacids. These first protective characteristics that have been observed in both ischemia with cellular ATP depletion models, suggest the utilization of aminoacids glycine or taurine in diabetic patient in order to avoid the development of microinfarcts. [source] A Moment Dead, a Moment Alive: How a Situational Personhood Emerges in the Vegetative State in an Israeli Hospital UnitAMERICAN ANTHROPOLOGIST, Issue 1 2010Nurit Bird-David ABSTRACT, Here we address the personhood of patients in a permanent vegetative state (PVS), who fall outside categories of "alive" or "dead" and "subject" or "object." Drawing on fieldwork in an Israeli hospital, we examine multiple and shifting approaches to PVS patients, which are articulated in the course of caring for and living with them. We argue that, alongside the institutional definition of these patients as being in a PVS, which, as Kaufman showed, evokes irresolvable confusion as to their ontological nature, there appear and disappear other senses of their personhood. Allying with other studies of cognitively impaired patients (e.g., those with dementia and Alzheimer's), we explore this relational person-concept while demonstrating its situational nature. We analyze patients' admission to the hospital, showing how their essentialistic personhood is "emptied" and how and when their fluid, relational personhood appears and disappears, further showing how this personhood is reified by imagined life stories. [source] Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disordersMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 2 2006Silvia Mandel Abstract Neurodegeneration in Parkinson's, Alzheimer's, or other neurodegenerative diseases appears to be multifactorial, where a complex set of toxic reactions, including oxidative stress (OS), inflammation, reduced expression of trophic factors, and accumulation of protein aggregates, lead to the demise of neurons. One of the prominent pathological features is the abnormal accumulation of iron on top of the dying neurons and in the surrounding microglia. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. The observations that iron induces aggregation of inert ,-synuclein and beta-amyloid peptides to toxic aggregates have reinforced the critical role of iron in OS-induced pathogenesis of neurodegeneration, supporting the notion that a combination of iron chelation and antioxidant therapy may be one significant approach for neuroprotection. Tea flavonoids (catechins) have been reported to possess divalent metal chelating, antioxidant, and anti-inflammatory activities, to penetrate the brain barrier and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. This review aims to shed light on the multipharmacological neuroprotective activities of green tea catechins with special emphasis on their brain-permeable, nontoxic, transitional metal (iron and copper)-chelatable/radical scavenger properties. [source] Review: Autophagy in neurodegeneration: firefighter and/or incendiarist?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2009A. Rami Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membrane autophagosomes, which subsequently fuse with lysosomes where their contents are degraded. This system has been implicated in various physiological processes including protein and organelle turnover, stress response, cellular differentiation, programmed cell death and pathological conditions. Defects in the autophagy machinery might have several consequences, as they have been associated with neurodegenerative disease and different forms of cancer. Thus, autophagy occupies a crucial position within the cell's metabolism, and its modulation may represent an alternative therapeutic strategy in several pathological settings including stroke, Alzheimer's, Huntington's, Parkinson's diseases and cancer. Recently, research has begun to identify some characteristics of neuronal autophagy. The results suggest that autophagy may provide a neuroprotective mechanism. However, there is evidence showing that dysfunction of autophagy in certain pathological situations can trigger and mediate programmed cell death. Autophagy has also been defined as prime suspect cause of non-apoptotic cellular demise. However, there is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell death and cell survival. It will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death programme and thus contribute to cell death. Many questions are open. Is autophagy a direct death execution pathway? Is autophagy an innocent bystander? Is autophagy a defence mechanism or just a scavenger or self-clearance tool in the cell? A profound understanding of the biological effects and the mechanisms underlying autophagy in neurones might be helpful in seeking effective new treatments for neurodegenerative diseases. Here, we review the defining characteristics of autophagy with special attention to its role in neurodegenerative disorders, and recent efforts to delineate the pathway of autophagic protein degradation in neurone. [source] The ubiquitin protein catabolic disordersNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2001Robert Layfield The ubiquitin,proteasome system of intracellular proteolysis is essential for cell viability. We propose the concept that neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other conditions including some types of cancer, collectively represent a raft of ,ubiquitin protein catabolic disorders' in which altered function of the ubiquitin,proteasome system can cause or directly contribute to disease pathogenesis. Genetic abnormalities within the ubiquitin pathway, either in ubiquitin-ligase (E3) enzymes or in deubiquitinating enzymes, cause disease because of problems associated with substrate recognition or supply of free ubiquitin, respectively. In some cases, mutations in protein substrates of the ubiquitin,proteasome system may directly contribute to disease progression because of inefficient substrate recognition. Mutations in transcripts for the ubiquitin protein itself (as a result of ,molecular misreading') also affect ubiquitin-dependent proteolysis with catastrophic consequences. This has been shown in Alzheimer's disease and could apply to other age-associated neurodegenerative conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin-dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases. [source] Roles of Vitamins E and C on Neurodegenerative Diseases and Cognitive PerformanceNUTRITION REVIEWS, Issue 10 2002Antonio Martin Demographic changes, together with improvements in nutrition, general health, and life expectancy, will greatly change the social and economic structures of most industrialized and developing countries in the next 50 years. Extended life expectancy has increased the number of chronic illnesses and disabilities, including cognitive impairments. Inflammatory processes and vascular dysfunctions appear to play important roles in the pathogenesis of age-associated pathologies including Alzheimer's and Parkinson's disease. A large body of evidence shows that both vitamins E and C are important for the central nervous system and that a decrease in their concentrations causes structural and functional damage to the cells. Several studies reveal a link between diets rich in fruits and vegetables containing generous amounts of vitamins E and C and lower incidence of certain chronic diseases. [source] | ||||||||||||||||||||||||||||||||||