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      Amyloid-Beta Mediates Homeostatic Synaptic Plasticity

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          Abstract

          The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP −/− mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β and not by APPsα, and it is neither observed in APP +/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca 2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased amyloid-β levels.

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          The self-tuning neuron: synaptic scaling of excitatory synapses.

          Gina G Turrigiano (2008)
          Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of all of a neuron's excitatory synapses up or down to stabilize firing. Current evidence suggests that neurons detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional mechanisms may allow local or network-wide changes in activity to be sensed through parallel pathways, generating a nested set of homeostatic mechanisms that operate over different temporal and spatial scales.
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            APP processing and synaptic function.

            Flavio Kamenetz, Taisuke Tomita, Helen V. Hsieh … (2003)
            A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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              Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.

              Ganesh Shankar, Shaomin Li, Tapan Mehta … (2008)
              Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Abeta from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Abeta dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Abeta N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Abeta dimers, suggesting that plaque cores are largely inactive but sequester Abeta dimers that are synaptotoxic. We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Neurosci
                Journal ID (iso-abbrev): J Neurosci
                Journal ID (hwp): jneuro
                Journal ID (pmc): jneurosci
                Journal ID (publisher-id): J. Neurosci
                Title: The Journal of Neuroscience
                Publisher: Society for Neuroscience
                ISSN (Print): 0270-6474
                ISSN (Electronic): 1529-2401
                Publication date (Print): 16 June 2021
                Publication date PMC-release: 16 June 2021
                Volume: 41
                Issue: 24
                Pages: 5157-5172
                Affiliations
                [1] 1Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
                [2] 2Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
                [3] 3Institute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Neuroscience Center, Goethe-University Frankfurt, 60590 Frankfurt, Germany
                [4] 4Institute of Pharmacy and Molecular Biotechnology, Functional Genomics, Ruprecht-Karls University, 69120 Heidelberg, Germany
                [5] 5German Center for Neurodegenerative Diseases, 81377 Munich, Germany
                [6] 6Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany
                [7] 7Munich Cluster for Systems Neurology, 81377 Munich, Germany
                [8] 8Center Brain Links Brain Tools, University of Freiburg, 79110 Freiburg, Germany
                [9] 9Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
                Author notes
                Correspondence should be addressed to Andreas Vlachos at andreas.vlachos@ 123456anat.uni-freiburg.de

                Author contributions: C.G., U.C.M., T.D., and A.V. designed research; C.G., M.F., D.B., S.F.L., and A.V. performed research; C.G., M.F., and S.F.L. analyzed data; C.G., S.F.L., U.C.M., T.D., and A.V. edited the paper; C.G. and A.V. wrote the paper; C.B. and U.C.M. contributed unpublished reagents/analytic tools; A.V. wrote the first draft of the paper.

                Article
                Publisher ID: JN-RM-1820-20
                DOI: 10.1523/JNEUROSCI.1820-20.2021
                PMC ID: 8211553
                PubMed ID: 33926999
                SO-VID: b92d5986-d8e7-401e-b5f0-3c2cd7d2075a
                Copyright © Copyright © 2021 Galanis et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                Date received : 15 July 2020
                Date revision received : 2 March 2021
                Date accepted : 28 March 2021
                Funding
                Funded by: http://doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaft (DFG)
                Award ID: FOR1332
                Award ID: CRC/TRR 167
                Award ID: CRC1080
                Award ID: MU1457/14-1
                Funded by: http://doi.org/10.13039/501100002347Bundesministerium für Bildung und Forschung (BMBF)
                Award ID: OGEAM
                Funded by: Munich Cluster for Systems Neurology
                Award ID: EXC 2145 SyNergy- ID 390857198
                Categories
                Subject: Research Articles
                Subject: Development/Plasticity/Repair

                Keywords: alzheimer’s disease,amyloid-beta,app processing,homeostatic plasticity,sappalpha,secretases
                Data availability:
                Keywords: alzheimer’s disease, amyloid-beta, app processing, homeostatic plasticity, sappalpha, secretases

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