411 research outputs found

    Pleiotropic effects of statins on brain cells

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    Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual crosstalk between the two cell types, particularly the transport of cholesterol from its site of synthesis to its target loci in neuronal cells, discussing the multiple mechanistic aspects and transporter systems involved. Statins are next analyzed from the point of view of their chemical structure and its impingement on their pharmacological properties and permeability through cell membranes and the blood-brain barrier in particular. The following section then discusses the transcriptional effects of statins and the changes they induce in brain cell genes associated with a variety of processes, including cell growth, signaling and trafficking, uptake and synthesis of cholesterol. We review the effects of statins at the cellular level, analyzing their impact on the cholesterol composition of the nerve and glial cell plasmalemma, neurotransmitter receptor mobilization, myelination, dendritic arborization of neurons, synaptic vesicle release, and cell viability. Finally, the role of statins in disease is exemplified by Alzheimer and Parkinson diseases and some forms of epilepsy, both in animal models and in the human form of these pathologies.Fil: Sodero, Alejandro Omar. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Barrantes, Francisco Jose. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

    Dietary cholesterol effects on learning, memory and amyloid beta: Learning and memory effects on brain cholesterol and sulfatide levels

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    Recent studies have revealed ambiguous findings on the effects of dietary cholesterol on learning. In one study by Schreurs and coworkers it was reported that a 2% cholesterol diet had a positive effect on learning. However, it was realized that metals, specifically copper, could potentially exacerbate the aggregation of amyloid beta (Abeta), a protein associated with Alzheimer\u27s disease (AD) leading to the formation of Abeta plaques. In a subsequent publication by Sparks and Schreurs it was reported that a 2% cholesterol diet with the addition of 0.12 ppm copper had a detrimental effect on learning and resulted in the formation of Abeta plaques. To better understand the effects of cholesterol and copper on learning and to begin exploring cholesterol\u27s effect on memory we conducted a series of experiments.;In a first study, we investigated the effects of dietary cholesterol and copper on learning. Rabbits fed a diet varying in cholesterol concentration (0, 0.5, 1, and 2%) with 0.12 ppm copper added to the drinking water received Pavlovian conditioning during which levels of learning were assessed. Analysis of Abeta staining, showed a significant cholesterol concentration-dependent increase in the number of Abeta positive neurons in the cortex of the cholesterol-fed rabbits. Learning was significantly greater in the 2% cholesterol-fed rabbits over controls. The data suggested that dietary cholesterol may facilitate learning and memory in the absence of Abeta plaques.;Next, we investigated dietary cholesterol effects on memory retention. We showed that dietary cholesterol had an adverse effect on memory retention of a previously learned task. It is still debatable whether or not dietary cholesterol affects brain cholesterol levels and there are no studies investigating sulfatide levels. Our data suggest that although dietary cholesterol affects memory retention, it does not do so by directly affecting cholesterol or sulfatide levels in the brain, suggesting peripheral effects may be mediated through secondary mechanisms. On the other hand, our data show that brain levels of cholesterol and sulfatides do change as a function of learning and memory.;Finally, in light of these findings, we investigated whether the changes in brain cholesterol and sulfatide levels occurred as a result of a learning task alone and if they occurred quickly or required several months to develop as seen in our previous memory retention experiment. We found significant changes in sulfatide levels as a function of time but no changes as a function of learning in either brain cholesterol or sulfatide levels

    The role of IGF-1 in exercise to improve obesity-related cognitive dysfunction

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    Obesity is an important factor that threatens human health. The occurrence of many chronic diseases is related to obesity, and cognitive function decline often occurs with the onset of obesity. With the further prevalence of obesity, it is bound to lead to a wider range of cognitive dysfunction (ORCD). Therefore, it is crucial to suppress ORCD through intervention. In this regard, exercise has been shown to be effective in preventing obesity and improving cognitive function as a non-drug treatment. There is sufficient evidence that exercise has a regulatory effect on a growth factor closely related to cognitive function—insulin-like growth factor 1 (IGF-1). IGF-1 may be an important mediator in improving ORCD through exercise. This article reviews the effects of obesity and IGF-1 on cognitive function and the regulation of exercise on IGF-1. It analyzes the mechanism by which exercise can improve ORCD by regulating IGF-1. Overall, this review provides evidence from relevant animal studies and human studies, showing that exercise plays a role in improving ORCD. It emphasizes the importance of IGF-1, which helps to understand the health effects of exercise and promotes research on the treatment of ORCD

    LIPID SIGNALING IN BRAIN AGING AND ALZHEIMER\u27S DISEASE: PHARMACOLOGICALLY TARGETING CHOLESTEROL SYNTHESIS, TRANSPORT AND METABOLISM

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    The role cholesterol plays in the brain has long been underappreciated even though the brain contains a disproportionately high percentage of body cholesterol. Recent studies have found a link between the dysregulation of lipid metabolism and the risk of acquiring Alzheimer’s disease (AD) as well as a predisposition to cognitive decline. The goal of these studies was to elucidate the possible role lipid metabolism plays in pathological and normal brain aging by pharmacologically manipulating lipid metabolism and determining effects on key hippocampal biomarkers of AD and age-related cognitive decline. One series of experiments used an agonist (TO901317) to the liver X receptor (LXR) in two transgenic AD mouse models. Chronic LXR activation reduced AD associated pathology and improved cognitive performance in AD mouse models. However, long-term potentiation (LTP) was not enhanced and peripheral side effects were observed. In another series of experiments the effects of chronically inhibiting cholesterol synthesis on cognitive aging in rats was determined. Animals were treated with either of two commonly prescribed statins, simvastatin or atorvastatin. Simvastatin, the more lipophilic statin, increased LTP and reduced the duration of the afterhyperpolarization (AHP). In addition, simvastatin upregulated key genes of the cholesterol synthesis pathway in the hippocampus as revealed by microarray analyses, but was associated with impaired performance in the Morris Water Maze, a hippocampal dependent task. Atorvastatin, a less lipophilic statin, reduced the AHP, but did not affect LTP or cognitive performance. Atorvastatin modulated a very different set of genes and reduced brain cholesterol more than simvastatin. These results suggest that manipulation of cholesterol metabolism selectively modulates key aspects of AD and brain aging

    Toward Fulfilling the Promise of Molecular Medicine in Fragile X

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    Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.)National Institute of Mental Health (U.S.)FRAXA Research Foundatio

    Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

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    Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well

    Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer's disease.

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    Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies

    Adult Neurogenesis in Avian Auditory Cortex, Caudomedial Nidopallium (NCM): Lateralization and Effects of Statins

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    In the first part of this paper, we investigated the basic relationship between learning, memory and adult neurogenesis using zebra finches. We found that in the auditory cortex, the left hemisphere had more new neurons than the right hemisphere. This lateralization was correlated with song learning and memory. In the second part, we used juvenile zebra finches as a model organism to study the effects of Lipitor on learning, memory and neurogenesis. We found that Lipitor impaired song learning and memory storage. Lipitor treatments also changed the morphology of new neurons and size of old neurons, suggesting statins may affect neurons that are important to learning and memory during the critical learning period. In the last part, we investigated whether the degree of lipophilicity determines the effects of statins on memory and neurogenesis in adult birds. Our results showed that birds treated with hydrophilic pravastatin had weaker memory than control birds, suggesting that lipophilicity may not be the only factor that determines the effects of statins on memory

    Cognitive deficits in children iwth neurofibromatosis type 1: from recognition to treatment

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