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Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ₄₂ Oligomers and Protect Synapses

Li, Songlin and Hayden, Eric Y. and Garcia, Veronica J. and Fuchs, Dieu-Trang and Sheyn, Julia and Daley, David A. and Rentsendorj, Altan and Torbati, Tania and Black, Keith L. and Rutishauser, Ueli and Teplow, David B. and Koronyo, Yosef and Koronyo-Hamaoui, Maya (2020) Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ₄₂ Oligomers and Protect Synapses. Frontiers in Immunology, 11 . Art. No. 49. ISSN 1664-3224. PMCID PMC7005081. doi:10.3389/fimmu.2020.00049.

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Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ₄₂) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ₄₂ oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ₄₂ oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ₄₂ fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ₄₂ removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1⁺-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115⁺-monocyte-grafted APP_(SWE)/PS1_(ΔE9)-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ₄₂ oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.

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Rutishauser, Ueli0000-0002-9207-7069
Additional Information:© 2020 Li, Hayden, Garcia, Fuchs, Sheyn, Daley, Rentsendorj, Torbati, Black, Rutishauser, Teplow, Koronyo and Koronyo-Hamaoui. 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. Received: 15 October 2019; Accepted: 09 January 2020; Published: 31 January 2020. We thank Mia Oviatt for assistance with editing this manuscript and Prof. Jevgenij Raskatov for his helpful comments. This paper is dedicated to Dr. Salomon Moni Hamaoui and Lillian Jones Black, both of whom died from Alzheimer's disease. Data Availability Statement: The raw data and protocols used to generate datasets for this study are presented in the article text, figures and tables. Supplementary data are also available online. Extended data can be made available upon reasonable request from the corresponding author to any qualified researcher. Ethics Statement: The animal study was reviewed and approved by Cedars-Sinai Medical Center Institutional Animal Care and Use Committee (IACUC). Author Contributions: MK-H: study conception, design, study supervision, and final approval of the manuscript. SL: major experimental contributor, data acquisition and design. VG, YK, D–TF, JS, AR, and TT: experimental contributors with assistance from MK-H and SL. EH, JS, and DT: preparation of Aβ42 assemblies. DD: correlational analysis with guidance from MK-H. SL, VG, and MK-H: data analysis, interpretation, and presentation. MK-H, SL, EH, D–TF, TT, YK, UR, KB, and DT: discussion on intellectual content and manuscript editing. MK-H, SL, EH, VG, D–TF, UR, and DT: manuscript drafting, editing, and revisions. This study was supported by the BrightFocus Foundation A2013328S00 grant (formerly AHAF; MK-H), The Coins for Alzheimer's Research Trust (C.A.R.T; MK-H) Fund, NIH/NIA R01AG056478 and R01AG055865 (MK-H), The Cheryl and Haim Saban Foundation (MK-H), The Marciano Family Foundation (MK-H), National Natural Science Foundation of China 81671229, 81871032 (SL) and the National Center for Advancing Translational Sciences through CTSI (UL1TR000124; MK-H).
Funding AgencyGrant Number
BrightFocus FoundationA2013328S00
Coins for Alzheimer's Research TrustUNSPECIFIED
Cheryl and Haim Saban FoundationUNSPECIFIED
Marciano Family FoundationUNSPECIFIED
National Natural Science Foundation of China81671229
National Natural Science Foundation of China81871032
Subject Keywords:Alzheimer's disease, neurodegeneration, immunomodulation therapy, amyloid-beta, regeneration, synaptogenesis
PubMed Central ID:PMC7005081
Record Number:CaltechAUTHORS:20200406-120922382
Persistent URL:
Official Citation:Li S, Hayden EY, Garcia VJ, Fuchs D-T, Sheyn J, Daley DA, Rentsendorj A, Torbati T, Black KL, Rutishauser U, Teplow DB, Koronyo Y and Koronyo-Hamaoui M (2020) Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses. Front. Immunol. 11:49. doi: 10.3389/fimmu.2020.00049
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102350
Deposited By: Tony Diaz
Deposited On:06 Apr 2020 20:10
Last Modified:16 Nov 2021 18:11

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