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      Combined High-Pressure and Multiquantum NMR and Molecular Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta

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          Abstract

          Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3. The presence of these salt bridges is correlated with less extended structures in the N-terminal region of Aβ. Through density functional theory calculations, we demonstrate how the introduction of negatively charged phosphoserine 8 influences the network of adjacent salt bridges in Aβ and favors more extended N-terminal structures. Our data propose a structural mechanism for the Ser8-phosphorylation-promoted Aβ aggregation and define the N-terminal salt bridges as potential targets for anti-AD drug design.

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          Most cited references41

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          The amyloid hypothesis of Alzheimer's disease at 25 years

          Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
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            Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.

            Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.
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              Developing a molecular dynamics force field for both folded and disordered protein states

              Significance Many proteins that perform important biological functions are completely or partially disordered under physiological conditions. Molecular dynamics simulations could be a powerful tool for the structural characterization of such proteins, but it has been unclear whether the physical models (force fields) used in simulations are sufficiently accurate. Here, we systematically compare the accuracy of a number of different force fields in simulations of both ordered and disordered proteins, finding that each force field has strengths and limitations. We then describe a force field that substantially improves on the state-of-the-art accuracy for simulations of disordered proteins without sacrificing accuracy for folded proteins, thus broadening the range of biological systems amenable to molecular dynamics simulations.
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                Author and article information

                Journal
                J Phys Chem Lett
                J Phys Chem Lett
                jz
                jpclcd
                The Journal of Physical Chemistry Letters
                American Chemical Society
                1948-7185
                07 October 2021
                14 October 2021
                : 12
                : 40
                : 9933-9939
                Affiliations
                []Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry , Göttingen 37077, Germany
                []Institute for Chemistry and Biology of the Marine Environment, University of Oldenburg , Oldenburg 26129, Germany
                [§ ]Department of Neurology, University Medical Center Göttingen , Göttingen 37075, Germany
                []Institute for Physical Biology, Heinrich Heine University , Düsseldorf 40225, Germany
                Author notes
                Author information
                https://orcid.org/0000-0002-1266-4344
                https://orcid.org/0000-0001-6935-6564
                Article
                10.1021/acs.jpclett.1c02595
                8521524
                34617758
                4291add9-76a0-4028-af2b-d27481bbe957
                © 2021 The Authors. Published by American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 08 August 2021
                : 04 October 2021
                Funding
                Funded by: Deutsche Forschungsgemeinschaft, doi 10.13039/501100001659;
                Award ID: RE 3655/2-1
                Funded by: Deutsche Forschungsgemeinschaft, doi 10.13039/501100001659;
                Award ID: RE 3655/2-3
                Categories
                Letter
                Custom metadata
                jz1c02595
                jz1c02595

                Physical chemistry
                Physical chemistry

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