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Morales I.,International Center for Biomedicine | Farias G.,International Center for Biomedicine | MacCioni R.B.,International Center for Biomedicine
NeuroImmunoModulation | Year: 2010

Evidence has been cumulated on the role of microglia cells deregulation and alterations in their interaction patterns with brain neurons, in the pathway towards neurodegeneration in Alzheimer's disease (AD). After the failure of the amyloid hypothesis to explain AD pathogenesis, current hypotheses focus on tau self-polymerization into pathological oligomers and filaments as a major culprit for neurofibrillary degeneration. It is worth pointing out that formation of tau polymers is consistent with the clinical and neuropathological observations, and that tangles are pathognomonic of AD and related tau disorders. In this context, inflammatory processes play a major role in neuronal degeneration. On the basis of studies on microglia and neuronal cultures, together with experiments in animal models, and the clinical evidence, we postulated that a series of endogenous damage signals activate microglia cells, inducing NFκ-β with the consequent release of cytokine mediators such as TNF-α, IL-6 and IL-1β. An overexpression of these mediators may trigger signaling cascades in neurons leading to activation of protein kinases gsk3β, cdk5, abl kinases, along with inactivation of phosphatases such as PP1, with the resulting hyperphosphorylation and self-aggregation of tau protein into neurotoxic oligomeric species. © 2010 S. Karger AG, Basel.


Guzman-Martinez L.,University of Chile | Guzman-Martinez L.,International Center for Biomedicine | Farias G.A.,International Center for Biomedicine | Maccioni R.B.,University of Chile | Maccioni R.B.,International Center for Biomedicine
Archives of Medical Research | Year: 2012

Alzheimer's disease (AD) diagnosis still depends on the triad of clinical, imaging and neuropsychological testing. The development of accurate, easy to use and inexpensive biological markers for AD is a long-standing aspiration for researchers and the medical community. Here we describe some of the recent advances in the field of biomarkers, both in cerebrospinal fluid (CSF) and in peripheral blood. © 2012 IMSS.


Carrasco-Gallardo C.,International Center for Biomedicine | Carrasco-Gallardo C.,University of Chile | Farias G.A.,International Center for Biomedicine | Fuentes P.,University of Chile | And 3 more authors.
Archives of Medical Research | Year: 2012

Alzheimer's disease (AD) is a brain disorder displaying a prevalence and impact in constant expansion. This expansive and epidemic behavior is concerning medical and public opinion while focusing efforts on its prevention and treatment. One important strategy to prevent this brain impairment is based on dietary changes and nutritional supplements, functional foods and nutraceuticals. In this review we discuss the potential contributions of shilajit and complex B vitamins to AD prevention. We analyze the status of biological studies and present data of a clinical trial developed in patients with mild AD. Studies suggest that shilajit and its active principle fulvic acid, as well as a formula of shilajit with B complex vitamins, emerge as novel nutraceutical with potential uses against this brain disorder. © 2012 IMSS.


Farias G.A.,International Center for Biomedicine | Farias G.A.,University of Chile | Guzman-Martinez L.,International Center for Biomedicine | Guzman-Martinez L.,University of Chile | And 3 more authors.
Journal of Alzheimer's Disease | Year: 2014

Alzheimer's disease is a growing health problem worldwide. The pharmaceutical industry has not recently developed any new drugs that have had a significant impact on the natural history of the disease, so considerable attention has been given to nutraceuticals and nutritional bioactive compounds that can be obtained directly from diet or supplementation. These compounds may be able to modify physiopathological processes responsible for neurodegeneration and/or to have pro-cognitive properties. Here, we review current knowledge on the role of diet modifications, lipid and carbohydrates consumption, vitamin supplementation, and the possible effects of antioxidant and nutraceutical compounds with neuroprotective activity, in the prevention and treatment of Alzheimer's disease and related disorders.


Farias G.,University of Chile | Farias G.,International Center for Biomedicine | Farias G.,Hospital Del Salvador | Perez P.,University of Chile | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2012

Platelets are major reservoirs of circulating amyloid-β and amyloid-β protein precursor (AβPP) and have been postulated as a reliable source for biological markers of Alzheimer's disease (AD). We have recently demonstrated that tau is also present in platelets, and that there are differences in the electrophoretic patterns of platelet tau forms in AD subjects with respect to controls. Here, we demonstrate that modifications in platelet tau forms occur independently of age in a broad population of 104 neurologically healthy individuals. More interesting, a strong correlation of platelet markers with the degree of cognitive impairment was evidenced in a group of 47 AD patients in comparison with 19 cognitive healthy subjects. In our series, platelet tau forms ratio had a sensitivity of 75.7% and specificity of 73.7%, respectively. We also found that platelet tau displays a significantly higher correlation with the presence of AD than the analyses of platelet AβPP. © 2012 - IOS Press and the authors. All rights reserved.


Morales I.,University of Chile | Morales I.,International Center for Biomedicine | Jimenez J.M.,University of Chile | Jimenez J.M.,International Center for Biomedicine | And 4 more authors.
Journal of Alzheimer's Disease | Year: 2013

Neuroinflammation is a process related to the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Increasing sets of evidence support the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration, a process we are calling neuroimmunomodulation in AD. On the basis of the hypothesis that pathological tau aggregates induce microglial activation with the subsequent events of the neuroinflammatory cascade, we have studied the effects of tau oligomeric species and filamentous structures over microglial cells in vitro. Tau oligomers and fibrils were induced by arachidonic acid and then their actions assayed upon addition to microglial cells. We showed activation of the microglia, with significant morphological alterations as analyzed by immunofluorescence. The augmentation of nitrites and the proinflammatory cytokine IL-6 was evaluated in ELISA assays. Furthermore, conditioned media of stimulated microglia cells were exposed to hippocampal neurons generating altered patterns in these cells, including shortening of neuritic processes and cytoskeleton reorganization. © 2013 - IOS Press and the authors. All rights reserved.


Neumann K.,University of Chile | Farias G.,University of Chile | Farias G.,International Center for Biomedicine | Slachevsky A.,International Center for Biomedicine | And 5 more authors.
Journal of Alzheimer's Disease | Year: 2011

Platelets are a major peripheral reservoir of the amyloid-β protein precursor, so they have been considered as a potential biological marker of Alzheimer's disease (AD). Here, it is demonstrated that tau protein is also present in platelets and that the levels of oligomeric species of this protein could serve as a novel and reliable biological marker for AD. Blood samples were obtained from 15 AD patients and 10 paired-age controls and platelets were separated via differential centrifugation. The purity of platelets was determined by flow cytometry and microscopy and the presence of tau was determined by immunofluorescence and immunoblots with tau specific antibodies. Immunofuorescence and immunoblot patterns of platelets were positive for tau. Immunoblots also showed the presence of high molecular weight (HMW) variants of tau that appeared to correspond to oligomeric forms of the protein. The ratio of HMW tau respect to tau monomeric species was significantly higher in AD patients than controls. The present is the first description of the presence of tau in platelets. The analysis of different tau fractions in platelets could serve as a new biological marker for AD. © 2011 - IOS Press and the authors. All rights reserved.


Fuentes P.,University of Chile | Catalan J.,International Center for Biomedicine
Current Alzheimer Research | Year: 2011

Alzheimer's Disease (AD) physiopathology is not yet totally established. Nevertheless it is known that a metabolism dysfunction of the amyloid beta precursor protein (APP) and the abnormal tau protein phosphorylation lead to the formation of neuritic plaques and neurofibrillary tangles, respectively. These events finally drive to the clinical expression of dementia. Formally approved during the past decade, treatments for AD are lacking of an updating, being essentially symptomatic. Anticholinesterase agents have failed in providing a substantial improvement in the mental health condition of AD patients. On the other hand, antiamyloid strategies, have failed in their efficacy or security on their last development phases. In this context, tau represents a potential therapeutic target, by the action of drugs that diminish its aggregation, or acting by altering its phosphorylation or filaments formation. There is also anti-tau miscellaneous strategies such as normal microtubule-stabilizing agents. Thus, it might be possible that in a near future the neurodegenerative process could be stopped. © 2011 Bentham Science Publishers.


PubMed | Institute of Neurosurgery Asenjo, University of Chile, International Center for Biomedicine and University of Pittsburgh
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2016

Intracellular neurofibrillary tangles are part of the core pathology of Alzheimers disease (AD), which are mainly composed of hyperphosphorylated tau protein.The purpose of this study is to determine whether high molecular weight (HMW) or low molecular weight (LMW) tau protein levels, as well as the ratio HMW/LMW, present in platelets correlates with brain magnetic resonance imaging (MRI) structural changes in normal and cognitively impaired subjects.We examined 53 AD patients and 37 cognitively normal subjects recruited from two Memory Clinics at the Universidad de Chile. Tau levels in platelets were determined by immunoreactivity and the MRI scans were analyzed using voxel-based morphometry in 41 AD patients.The HMW/LMW tau ratio was statistically different between controls and AD patients, and no associations were noted between HMW or LMW tau and MRI structures. In a multivariate analysis controlled for age and education level, the HMW/LMW tau ratio was associated with reduced volume in the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region.This exploratory study showed that HMW/LMW tau ratio is significantly higher in AD patients than control subjects, and that it is associated with specific brain regions atrophy. Determination of peripheral markers of AD pathology can help understanding the pathophysiology of neurodegeneration in AD.


News Article | December 22, 2016
Site: www.eurekalert.org

December 22nd, 2016 - A discovery of high relevance in medical research will be published in Volume 55, number 4 of December 2016 of the prestigious "Journal of Alzheimer's Disease (JAD)", entitled "Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer's Disease". This paper has been highlighted as one of the most important contribution to this field. The paper stems from a fruitful collaboration between the neuroscience laboratory from the International Center for Biomedicine (ICC) under the leadership of Dr. Ricardo Maccioni and the research teams of Drs. Andrea Slachevsky, Faculty of Medicine, University of Chile, together with Drs. Oscar Lopez and James Becker from University of Pittsburgh, School of Medicine, USA. Drs. Maccioni and Farías have pioneered the technology that detects in human blood platelets the pathological oligomeric forms of brain tau protein in patients with Alzheimer's disease (AD) and other neurodegenerative disorders. More importantly, the ratio between this anomalous tau and the normal tau protein can discriminate AD patients from normal controls, and are associated with decreased cognitive impairment. These studies open a new avenue in the development of highly sensitive and efficient biomarkers for neurodegenerative disorders. The fact that pathological forms of tau proteins in platelets correlated with decreased brain volume in areas known to be associated with AD pathology in the brain is one step forward for the use of peripheral biomarkers, not only for clinical purposes, but also for research studies oriented to understand the complexity of AD pathology. This article, highlighted by JAD, proved that the relationship between the pathological and normal variants of tau were associated with the reduction of cerebral volume in key structures linked with the disease. These structures included the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region, in agreement with MRI neuroimaging approaches. In addition to the enormous utility of this non-invasive technology for the detection and progression of AD, the use of a tau biomarker could lead to the identification of AD pathology before the clinical symptoms are evident, and it could play an essential role in the development of preventive therapies. Moreover, the determination of peripheral tau markers in platelets can contribute to the understanding of the pathophysiology of multiple neurodegenerative processes where tau proteins play a critical role. The Journal of Alzheimer's Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 4.151 according to Thomson Reuters' 2014 Journal Citation Reports. The Journal is published by IOS Press.

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