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      A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

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          Abstract

          Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

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          Neural mechanisms of ageing and cognitive decline.

          During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
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            Place navigation impaired in rats with hippocampal lesions.

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              A Simple Role for BDNF in Learning and Memory?

              Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                14 December 2011
                : 6
                : 12
                : e27865
                Affiliations
                [1 ]Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America
                [2 ]Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America
                [3 ]Laboratory of Pharmacology, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo-shi, Tokyo, Japan
                [4 ]Molecular Neurosciences, The Scripps Research Institute, La Jolla, California, United States of America
                [5 ]Laboratorium f. Physikalische Chemie, ETH Zurich, Zurich, Switzerland
                Thomas Jefferson University, United States of America
                Author notes

                Conceived and designed the experiments: MP QC PM AR DS. Performed the experiments: MP QC RD PM AR RR CE CC TA KA DS. Analyzed the data: MP QC AR RR TA KA DS. Contributed reagents/materials/analysis tools: AR RR TA KA DS. Wrote the paper: MP QC AR PM DS.

                Article
                PONE-D-11-19517
                10.1371/journal.pone.0027865
                3237323
                22194796
                23e6d8f7-3ab4-47f1-94f7-159fc1a986d2
                Chen et al. 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
                : 3 October 2011
                : 26 October 2011
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Biochemistry
                Neurochemistry
                Synaptic Plasticity
                Proteins
                Growth Factors
                Immune System Proteins
                Protein Interactions
                Chemical Biology
                Drug Discovery
                Small Molecules
                Biotechnology
                Drug Discovery
                Small Molecules
                Neuroscience
                Cellular Neuroscience
                Neuronal Morphology
                Cognitive Neuroscience
                Cognition
                Working Memory
                Molecular Neuroscience
                Signaling Pathways
                Neurochemistry
                Neuromodulation
                Neurophysiology
                Central Nervous System
                Synapses
                Animal Cognition
                Learning and Memory
                Neurobiology of Disease and Regeneration
                Chemistry
                Medicinal Chemistry
                Medicine
                Neurology
                Dementia
                Alzheimer Disease
                Neurodegenerative Diseases

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                Uncategorized

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