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      Prion protein and aging

      review-article
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      Frontiers in Cell and Developmental Biology
      Frontiers Media S.A.
      PrP, aging, Alzheimer disease, prion diseases

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          Abstract

          The cellular prion protein (PrP C) has been widely investigated ever since its conformational isoform, the prion (or PrP Sc), was identified as the etiological agent of prion disorders. The high homology shared by the PrP C-encoding gene among mammals, its high turnover rate and expression in every tissue strongly suggest that PrP C may possess key physiological functions. Therefore, defining PrP C roles, properties and fate in the physiology of mammalian cells would be fundamental to understand its pathological involvement in prion diseases. Since the incidence of these neurodegenerative disorders is enhanced in aging, understanding PrP C functions in this life phase may be of crucial importance. Indeed, a large body of evidence suggests that PrP C plays a neuroprotective and antioxidant role. Moreover, it has been suggested that PrP C is involved in Alzheimer disease, another neurodegenerative pathology that develops predominantly in the aging population. In prion diseases, PrP C function is likely lost upon protein aggregation occurring in the course of the disease. Additionally, the aging process may alter PrP C biochemical properties, thus influencing its propensity to convert into PrP Sc. Both phenomena may contribute to the disease development and progression. In Alzheimer disease, PrP C has a controversial role because its presence seems to mediate β-amyloid toxicity, while its down-regulation correlates with neuronal death. The role of PrP C in aging has been investigated from different perspectives, often leading to contrasting results. The putative protein functions in aging have been studied in relation to memory, behavior and myelin maintenance. In aging mice, PrP C changes in subcellular localization and post-translational modifications have been explored in an attempt to relate them to different protein roles and propensity to convert into PrP Sc. Here we provide an overview of the most relevant studies attempting to delineate PrP C functions and fate in aging.

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          Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

          PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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            Alzheimer's disease as homeostatic responses to age-related myelin breakdown.

            The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin. Copyright © 2009 Elsevier Inc. All rights reserved.
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              Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein.

              Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-beta (Abeta) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Abeta are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Abeta-mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Abeta(1-42) oligomers impaired consolidation of the long-term recognition memory, whereas mature Abeta(1-42) fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Abeta antibody. It has been suggested that the cellular prion protein (PrP(C)) mediates the impairment of synaptic plasticity induced by Abeta. We confirmed that Abeta(1-42) oligomers interact with PrP(C), with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Abeta(1-42) oligomers are responsible for cognitive impairment in AD and that PrP(C) is not required.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                18 July 2014
                29 August 2014
                2014
                : 2
                : 44
                Affiliations
                Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati Trieste, Italy
                Author notes

                Edited by: Sophie Mouillet-Richard, INSERM Unit 1124, France

                Reviewed by: Mohammed Moudjou, Institut National de la Recherche Agronomique, France; Inga Zerr, University Medical Center Göttingen, Germany

                *Correspondence: Giuseppe Legname, Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, Trieste 34136, Italy e-mail: legname@ 123456sissa.it

                This article was submitted to Cell Death and Survival, a section of the journal Frontiers in Cell and Developmental Biology.

                Article
                10.3389/fcell.2014.00044
                4207048
                25364751
                ce7161f2-b8e7-4be3-b4fe-2da7f40ca3c5
                Copyright © 2014 Gasperini and Legname.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 June 2014
                : 09 August 2014
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 108, Pages: 8, Words: 8308
                Categories
                Cell and Developmental Biology
                Review Article

                prp,aging,alzheimer disease,prion diseases
                prp, aging, alzheimer disease, prion diseases

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