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      Ferulic Acid Is a Nutraceutical β-Secretase Modulator That Improves Behavioral Impairment and Alzheimer-like Pathology in Transgenic Mice

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          Abstract

          Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in brains of Alzheimer’s disease (AD) patients. Recent AD therapeutic interest has been directed toward a group of anti-amyloidogenic compounds extracted from plants. We orally administered the brain penetrant, small molecule phenolic compound ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated behavioral impairment and AD-like pathology. Oral FA treatment for 6 months reversed transgene-associated behavioral deficits including defective: hyperactivity, object recognition, and spatial working and reference memory, but did not alter wild-type mouse behavior. Furthermore, brain parenchymal and cerebral vascular β-amyloid deposits as well as abundance of various Aβ species including oligomers were decreased in FA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, reduced β-site APP cleaving enzyme 1 protein stability and activity, attenuated neuroinflammation, and stabilized oxidative stress. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a β-secretase modulator with therapeutic potential against AD.

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          Most cited references61

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          A specific amyloid-beta protein assembly in the brain impairs memory.

          Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
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            Inflammation and Alzheimer's disease.

            Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
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              Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

              Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                8 February 2013
                : 8
                : 2
                : e55774
                Affiliations
                [1 ]Department of Biomedical Sciences, Saitama Medical Center and University, Kawagoe, Saitama, Japan
                [2 ]Department of Pathology, Saitama Medical Center and University, Kawagoe, Saitama, Japan
                [3 ]Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
                [4 ]Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsoni College of Medicine, University of South Florida, Tampa, Florida, United States of America
                [5 ]Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsoni College of Medicine, University of South Florida, Tampa, Florida, United States of America
                [6 ]Regenerative Medicine Institute Neural Program, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
                [7 ]Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America
                Boston University School of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TM TT. Performed the experiments: TM NK M-VG-S JT TT. Analyzed the data: TM M-VG-S TT. Wrote the paper: TM TT.

                Article
                PONE-D-12-28953
                10.1371/journal.pone.0055774
                3568151
                23409038
                d5e054bd-9410-471c-bdc5-cc2b805895c5
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 September 2012
                : 4 January 2013
                Page count
                Pages: 16
                Funding
                National Institute of Neurological Disorders and Stroke(5R00AG029726-04, 3R00AG029726-04S1, and 1R01NS076794-01) to T.T., Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (22500320) to T.M., Alzheimer’s Association Zenith Fellows Award (ZEN-10-174633) to T.T., and an American Federation of Aging Research/Ellison, and Medical Foundation Julie Martin Mid-Career Award in Aging Research (M11472) to T.T. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immune System
                Immunopathology
                Model Organisms
                Animal Models
                Mouse
                Neuroscience
                Animal Cognition
                Behavioral Neuroscience
                Learning and Memory
                Chemistry
                Medicinal Chemistry
                Medicine
                Neurology
                Dementia
                Alzheimer Disease
                Neurodegenerative Diseases

                Uncategorized
                Uncategorized

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