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      Aβ Seeding as a Tool to Study Cerebral Amyloidosis and Associated Pathology

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          Abstract

          Misfolded proteins can form aggregates and induce a self-perpetuating process leading to the amplification and spreading of pathological protein assemblies. These misfolded protein assemblies act as seeds of aggregation. In an in vivo exogenous seeding model, both the features of seeds and the position at which seeding originates are precisely defined. Ample evidence from studies on intracerebal injection of amyloid-beta (Aβ)-rich brain extracts suggests that Aβ aggregation can be initiated by prion-like seeding. In this mini-review article, we will summarize the past and current literature on Aβ seeding in mouse models of AD and discuss its implementation as a tool to study cerebral amyloidosis and associated pathology.

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          Most cited references70

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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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            An analytical solution to the kinetics of breakable filament assembly.

            We present an analytical treatment of a set of coupled kinetic equations that governs the self-assembly of filamentous molecular structures. Application to the case of protein aggregation demonstrates that the kinetics of amyloid growth can often be dominated by secondary rather than by primary nucleation events. Our results further reveal a range of general features of the growth kinetics of fragmenting filamentous structures, including the existence of generic scaling laws that provide mechanistic information in contexts ranging from in vitro amyloid growth to the in vivo development of mammalian prion diseases.
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              The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease

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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                02 October 2019
                2019
                : 12
                : 233
                Affiliations
                [1] 1Department of Neurology/Neurodegeneration, Medical Center—University of Freiburg , Freiburg, Germany
                [2] 2Faculty of Medicine, University of Freiburg , Freiburg, Germany
                [3] 3Faculty of Biology, University of Freiburg , Freiburg, Germany
                [4] 4Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg , Freiburg, Germany
                Author notes

                Edited by: Tiago F. Outeiro, University Medical Center Goettingen, Germany

                Reviewed by: Charles Robert Harrington, University of Aberdeen, United Kingdom; Ehud Cohen, Hebrew University of Jerusalem, Israel

                *Correspondence: Melanie Meyer-Luehmann melanie.meyer-luehmann@ 123456uniklinik-freiburg.de
                Article
                10.3389/fnmol.2019.00233
                6783493
                31632238
                e222e3bc-a1c2-464c-92f7-026dd58b68c3
                Copyright © 2019 Friesen and Meyer-Luehmann.

                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) and the copyright owner(s) 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
                : 09 July 2019
                : 11 September 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 142, Pages: 9, Words: 8302
                Categories
                Neuroscience
                Mini Review

                Neurosciences
                alzheimer’s disease,cerebral amyloidosis,amyloid plaques,aβ seeding,cross-seeding
                Neurosciences
                alzheimer’s disease, cerebral amyloidosis, amyloid plaques, aβ seeding, cross-seeding

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