1.
Resveratrol Protects Rats from Aβ-induced Neurotoxicity by the Reduction of iNOS Expression and Lipid Peroxidation.
Source
Department of Biochemical Science and Biotechnology, National Chia-Yi University, Chia-Yi, Taiwan.
Abstract
Alzheimer disease (AD) is an age-dependent neurodegenerative disease characterized by the formation of β-amyloid (Aβ)-containing senile plaque. The disease could be induced by the administration of Aβ peptide, which was also known to upregulate inducible nitric oxide synthase (iNOS) and stimulate neuronal apoptosis. The present study is aimed to elucidate the cellular effect of resveratrol, a natural phytoestrogen with neuroprotective activities, on Aβ-induced hippocampal neuron loss and memory impairment. On adult Sprague-Dawley rats, we found the injection of Aβ could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1). By combining the treatment with Aβ, resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1. Moreover, the similar neurological and cellular response were also observed when Aβ treatment was combined with the administration of a NOS inhibitor, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME). These findings strongly implicate that iNOS is involved in the Aβ-induced lipid peroxidation and HO-1 downregulation, and resveratrol protects animals from Aβ-induced neurotoxicity by suppressing iNOS production.
- PMID:
- 22220203
- [PubMed - in process]
Tannic Acid is a Natural β-secretase Inhibitor that Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice.
Source
Saitama Medical Center and University, Japan;
Abstract
Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally-occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter non-transgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology.
- PMID:
- 22219198
- [PubMed - as supplied by publisher]
Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging.
Source
Ethel Percy Andrus Gerontology Center, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90089-0191, USA, cefinch@usc.edu.
Abstract
At later ages, humans have high risk of developing Alzheimer disease (AD) which may afflict up to 50% by 90 years. While prosimians and monkeys show more substantial changes, the great apes brains examined show mild neurodegenerative changes. Compared with rodents, primates develop and reproduce slowly and are long lived. The New World primates contain some of the shortest as well as some of the longest-lived monkey species, while the prosimians develop the most rapidly and are the shortest lived. Great apes have the largest brains, slowest development, and longest lives among the primates. All primates share some level of slowly progressive, age-related neurodegenerative changes. However, no species besides humans has yet shown regular drastic neuron loss or cognitive decline approaching clinical grade AD. Several primates accumulate extensive deposits of diffuse amyloid-beta protein (Aβ) but only a prosimian-the gray mouse lemur-regularly develops a tauopathy approaching the neurofibrillary tangles of AD. Compared with monkeys, nonhuman great apes display even milder brain-aging changes, a deeply puzzling observation. The genetic basis for these major species differences in brain aging remains obscure but does not involve the Aβ coding sequence which is identical in nonhuman primates and humans. While chimpanzees merit more study, we note the value of smaller, shorter-lived species such as marmosets and small lemurs for aging studies. A continuing concern for all aging studies employing primates is that relative to laboratory rodents, primate husbandry is in a relatively primitive state, and better husbandry to control infections and obesity is needed for brain aging research.
- PMID:
- 22218781
- [PubMed - as supplied by publisher]
Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex.
Source
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract
Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC(50)) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs.
Copyright © 2011 Elsevier Inc. All rights reserved.
- PMID:
- 22217416
- [PubMed - as supplied by publisher]
Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.
Source
Exploratory and Translational Sciences, Merck Research Laboratories, Merck Inc., West Point, Pennsylvania, United States of America.
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression.
- PMID:
- 22216330
- [PubMed - in process]
- PMCID: PMC3247273
Assay to Measure Oxidized and Reduced Forms of CoQ by LC-MS/MS.
Source
Seattle Children's Hospital Research Institute, Seattle, WA, USA, sihahn@uw.edu.
Abstract
The redox status of mitochondrial coenzyme Q (CoQ) is an important marker for oxidative stress associated with several disorders such as Parkinson disease and Alzheimer disease. Altered redox status may be present in mitochondrial electron transport complex disorders. Intracellular CoQ levels reflect the functional status of the mitochondrial electron transport complex better than plasma levels. Here, we describe the method to determine the reduced and oxidized form of CoQ in white blood cells using LC-MS/MS.
- PMID:
- 22215547
- [PubMed - in process]
Determinants of Care Costs of Patients With Dementia or Cognitive Impairment.
Source
*Alzheimer Centre Limburg, School for Mental Health and Neuroscience (MHeNS), University Medical Centre, AZ Maastricht †Department of Health Organization, Policy and Economics, Faculty of Health Medicine and Life Sciences, CAPHRI School for Public Health and Primary Care, Maastricht University, MD Maastricht ‡Institute of Health Policy and Management, Erasmus University Rotterdam, DR Rotterdam, The Netherlands.
Abstract
INTRODUCTION:
Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to support allocation of resources are often developed making use of cost-of-illness (COI) studies. However, current COI study estimates are highly variable due to care setting and methodological issues. We aim to explore variables explaining the variation of (formal and informal) health care costs of cognitive disorders, using a broad spectrum of variables, including patient, caregiver, and social context variables.
METHODS:
A bottom-up COI study design was used in which a societal viewpoint and a validated method to measure and value informal care was applied. Data were analyzed using univariate, multivariate, and forward regression analyses.
RESULTS:
The average 1-year health care sector costs were &OV0556;26,140 ($34,505 or £17,775) and &OV0556;11,931 ($15,749 or £8113) for patient and family. The analyses indicated that cognitive functioning, caregiver burden, patient sex, and instrumental activities of daily living were significantly associated with care costs independently.
CONCLUSIONS:
Cognitive functioning and instrumental activities of daily living are important variables to include in health care decision models. We recommend also including caregiver burden and patient sex in decision models for health policy decision makers to fully reflect the heterogeneity of the disease progression of cognitive disorders.
- PMID:
- 22214890
- [PubMed - as supplied by publisher]
Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by 11C-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining 11C-Pittsburgh Compound B and 18F-FDG.
Source
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Abstract
Astrocytes colocalize with fibrillar amyloid-β (Aβ) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar Aβ. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using (11)C-deuterium-L-deprenyl ((11)C-DED) to measure monoamine oxidase B located in astrocytes. Along with (11)C-DED PET, (11)C-Pittsburgh compound B ((11)C-PIB; fibrillar Aβ deposition), (18)F-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients.
METHODS:
(11)C-DED PET was performed in MCI patients (n = 8; mean age ± SD, 62.6 ± 7.5 y; mean Mini Mental State Examination, 27.5 ± 2.1), AD patients (n = 7; mean age, 65.1 ± 6.3 y; mean Mini Mental State Examination, 24.4 ± 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 ± 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the (11)C-DED data. (11)C-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional (18)F-FDG uptake and (11)C-PIB retention were calculated for each patient, with cerebellar gray matter as a reference.
RESULTS:
ANOVA analysis of the regional (11)C-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high (11)C-PIB retention. Increased (11)C-DED binding in most cortical and subcortical regions was observed in MCI (11)C-PIB+ patients relative to controls, MCI (11)C-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers.
CONCLUSION:
Increased (11)C-DED binding throughout the brain of the MCI (11)C-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.
Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.
Source
Neuropsychiatric Clinic, Skåne University Hospital, S-20502 Malmö, Sweden. oskar.hansson@med.lu.se.
Abstract
CONTEXT:
Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.
OBJECTIVES:
To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.
DESIGN:
A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).
SETTING:
Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure Conversion to AD dementia.
RESULTS:
During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.
CONCLUSIONS:
Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
Contributions of the Framingham Heart Study to Stroke and Dementia Epidemiologic Research at 60 Years.
Source
Medicine, and Public Health, Boston University School of Medicine, Boston, Massachusetts.
Abstract
The Framingham Heart Study, the longest-running prospective epidemiologic study in history, was initiated in 1948 in response to the rising toll of coronary heart disease and hypertension. During the ensuing decades, the study of otherdiseases, notably stroke and dementia, was added. In 1971, 5124 offspring of the original cohort of 5209 men and women were added, and a third generation of 4095 men and women were added in 2002. The 3-generation structure was used to relate a host of risk factors measured in mid and late life to the subsequent development of stroke, dementia, and cognitive decline. It has also facilitated studies of family occurrence of disease over generations particularly for genomic research. Dementia and Alzheimer disease research has proceeded from the determination of risk factors for at least moderately severe Alzheimer disease in the first generation to mild cognitive impairment and mild Alzheimer disease in the offspring and to studies of the third generation for detection of pre-mild cognitive impairment and indicators of cognitive decline in mid life. These research efforts have been facilitated by genome-wide association studies, biomarkers, and multiple measures of subclinical vascular disease. The tempo of decline has been documented by serial quantitative measures of brain structure on magnetic resonance imaging and cognitive performance by neuropsychological testing. Clinical correlation with systematic neuropathological examinations of more than 150 brains has provided important confirmation of cerebrovascular and brain tissue indices of disease. Identification of persons at heightened risk for stroke, mild cognitive impairment, Alzheimer disease, and cognitive decline years prior to diseaseonset may facilitate delay in disease onset and prevention.
Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study.
Source
Human Nutrition Research Center on Aging, Tufts University (Drs Van Himbergen, Ai, Thongtang, and Schaefer and Ms Otokozawa), Department of Neurology, School of Medicine (Drs Beiser, Seshadri, Au, and Wolf), and Department of Biostatistics, School of Public Health (Dr Beiser), Boston University, and the National Heart, Lung, and Blood Institute Framingham Heart Study (Drs Beiser, Seshadri, Au, and Wolf), Boston, Massachusetts.
Abstract
OBJECTIVE:
To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
DESIGN:
Prospective cohort study.
SETTING:
Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia.
PARTICIPANTS:
Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
MAIN OUTCOME MEASURES:
We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
RESULTS:
Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median.
CONCLUSION:
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients.
Source
Prof. Danuta Maślińska, Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego St, 02-106 Warsaw, Poland, phone +48 22 608 65 02, fax +48 22 608 65 02, e-mail: maslinskad@cmdik.pan.pl.
Abstract
RAGE (receptor for advanced glycation end-products) participates in the influx transport of glycated Aβ (amyloid beta) from the blood to the brain. Because little is known of the RAGE operating in brain barriers such as those in the choroid plexus and ependyma, the aim of the present study was to examine the immunodistributions of RAGE and Aβ peptides in the choroid plexus where the blood-cerebrospinal fluid barrier (B-CSF) is located, and in ependyma of the brain ventricles associated with functions of the cerebrospinal fluid-brain barrier (CSF-B). The study was performed on patients over 65 years successfully resuscitated after cardiac arrest with survival a few weeks. The control group consisted of age-matched individuals who were not resuscitated and died immediately after cardiac arrest. In resuscitated patients, but not in controls, RAGE receptors were localized in choroid plexus (CP) epithelial cells and in ependymal cells bordering the brain ventricles. These cells form the B-CSF and CSF-B barriers. The presence of Aβ was detected within the CP blood vessels and in the basement membrane of the CP epithelium. In numerous cytoplasmic vacuoles of CP epithelial and ependymal cells Aβ protein was found and our observations suggest that the contents of those vacuoles were undergoing progressive digestion. The results demonstrated that CP epithelium and ependymal cells, equipped with RAGE receptors, not only play an important role in the creation of amyloid deposits in the brain but are also places where Aβ may be utilized. The RAGE transportation system should be a main target in the therapy of brain amyloidosis, a well-known risk factor of Alzheimer disease.
Divergent clinical and neuropathological phenotype in a Gerstmann-Sträussler-Scheinker P102L family.
Source
Department of Genetics and Pathology, Rudbeck's Laboratory, Uppsala University, Uppsala, Sweden.
Abstract
OBJECTIVES:
Gerstmann-Sträussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene.
MATERIALS AND METHODS:
Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three.
RESULTS:
Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom.
CONCLUSIONS:
This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann-Sträussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology.
© 2012 John Wiley & Sons A/S.
Fermented Grape Marc (FGM): Immunomodulating Properties and its Potential Exploitation in the Treatment of Neurodegenerative Diseases.
Source
Department of Basic Medical Sciences, University of Bari, Bari, Italy. jirillo@midim.uniba.it.
Abstract
The onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM-induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease.
- PMID:
- 22211687
- [PubMed - as supplied by publisher]
Immunopathogenesis of Neurodegenerative Diseases: Current Therapeutic Models of Neuroprotection with Special Reference to Natural Products.
Source
Department of Medical Sciences University of Bari, Bari, Italy. thea.magrone@libero.it.
Abstract
Parkinson disease (PD) and Alzheimer disease (AD) are neurodegenerative processes whose frequency is dramatically increasing in the western world. Both diseases share a common pathogenic denominator characterized by an exaggerated activation of the systemic and cerebral immune system, respectively. For instance, lipopolysaccharides in PD and amyloid beta in AD trigger microglia and astrocytes to release reactive oxygen species (ROS) and proinflammatory cytokines. Infiltrating peripheral T cells once activated in the central nervous system also contribute to the neurodegenerative process. Besides innovative biotherapy, nutraceuticals or functional foods are currently investigated for their neuroprotective activities. Especially, vitamin D and polyphenols, seem to be promising therapeutic tools for inhibiting ROS formation and arresting cytokine-mediated neuroinflammation in PD and AD.
- PMID:
- 22211682
- [PubMed - as supplied by publisher]
Perceptual and motor inhibitory abilities in normal aging and Alzheimer disease(AD): A preliminary study.
Source
Department of Psychology: Cognition and Behavior, University of Liège, Belgium; Fund for Scientific Research (F.R.S.-FNRS), Belgium.
Abstract
Deficits in inhibitory abilities are frequently observed in normal aging and AD. However, few studies have explored the generality of these deficits in a single group of participants. A battery of tasks assessing perceptual and motor inhibitory functioning was administered to young and older healthy participants (Study 1), as well as to mild Alzheimer patients (Study 2). Results did not agree with a selective impairment of motor or perceptual inhibition in either AD or normal aging but rather suggest that a decrease in cognitive resources available in working memory could explain inhibitory performance both in normal aging and AD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP).
Source
Deutsches Institut für DemenzPrävention (DIDP), Neurodegeneration and Neurobiology, 66421 Homburg, Germany.
Abstract
Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease.
Copyright © 2012 Elsevier Inc. All rights reserved.
Computational evidence to inhibition of human acetyl cholinesterase by withanolide a for Alzheimer treatment.
Source
Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016, India. sundar@dbeb.iitd.ac.in.
Abstract
Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. So far only five drugs have been approved by US FDA that temporarily slow worsening of symptoms for about six to twelve months. The limited number of therapeutic options for AD drives the exploration of new drugs. Enhancement of the central cholinergic function by the inhibition of acetylcholinesterase is a prominent clinically effective approach for the treatment of AD. Recently withanolide A, a secondary metabolite from the ayurvedic plant Withania somnifera has shown substantial neuro-protective ability. The present study is an attempt to elucidate the cholinesterase inhibition potential of withanolide A along with the associated binding mechanism. Our docking simulation results predict high binding affinity of the ligand to the receptor. Further, long de novo simulations for 10_ns suggest that ligand interaction with the residues Thr78, Trp81, Ser120 and His442 of human acetylcholinesterase, all of which fall under one or other of the active sites/subsites, could be critical for its inhibitory activity. The study provides evidence for consideration of withanolide A as a valuable small ligand molecule in treatment and prevention of AD associated pathology. The present information could be of high value for computational screening of AD drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of human acetylcholinesterase would further enhance the potential of such analysis in understanding the molecular interaction basis between ligand and receptor.
Abstracts of the Alzheimer's Imaging Consortium. July 16-21, 2011. Paris, France.
- PMID:
- 22207911
- [PubMed - indexed for MEDLINE]
Hippocampal Neuronal Atrophy and Cognitive Function in Delayed Poststroke and Aging-Related Dementias.
Source
From the Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK.
Abstract
BACKGROUND AND PURPOSE:
We have previously shown delayed poststroke dementia in elderly (≥75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown.
METHODS:
Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia,Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome.
RESULTS:
Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (P<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (P<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (P<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (P<0.05).
CONCLUSIONS:
Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease.
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