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      Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer's Disease Treatment: Rethinking the Current Strategy

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Alzheimer's disease (AD) is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (A β ) and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with A β and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

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          Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

          P Arriagada, J H Growdon, E T Hedley-Whyte … (1992)
          We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
          Article 0 comments Cited 610 times – based on 0 reviews     Review now
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            Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.

            Xinglong Wang, Bo Su, Hyoung-gon Lee … (2009)
            Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.
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              Long-term depression in the CNS.

              Graham L. Collingridge, Stéphane Peineau, John G. Howland … (2010)
              Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Alzheimers Dis
                Journal ID (iso-abbrev): Int J Alzheimers Dis
                Journal ID (publisher-id): IJAD
                Title: International Journal of Alzheimer's Disease
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-8024
                ISSN (Electronic): 2090-0252
                Publication date (Print): 2012
                Publication date (Electronic): 8 March 2012
                Volume: 2012
                Electronic Location Identifier: 630182
                Affiliations
                1Le Groupe de Recherche sur le Système Nerveux Central, Département de Physiologie, Université de Montréal, Montréal, QC, Canada
                2Douglas Mental Health University Institute, McGill University, Department of Psychiatry, Montreal, Quebec, Canada
                3UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
                4Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
                Author notes
                *Siddhartha Mondragón-Rodríguez: sidmonrod@ 123456gmail.com

                Academic Editor: Paula Moreira

                Article
                DOI: 10.1155/2012/630182
                PMC ID: 3310047
                PubMed ID: 22482074
                SO-VID: 40d82364-d7af-4eae-9ad2-9d5011a5bcbb
                Copyright © Copyright © 2012 Siddhartha Mondragón-Rodríguez et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 7 October 2011
                Date accepted : 18 November 2011
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Neurology
                Data availability:
                ScienceOpen disciplines: Neurology

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