AUTHOR=Li Songlin , Hayden Eric Y. , Garcia Veronica J. , Fuchs Dieu-Trang , Sheyn Julia , Daley David A. , Rentsendorj Altan , Torbati Tania , Black Keith L. , Rutishauser Ueli , Teplow David B. , Koronyo Yosef , Koronyo-Hamaoui Maya 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00049

DOI=10.3389/fimmu.2020.00049

ISSN=1664-3224

ABSTRACT=<p>Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ<sub>42</sub>) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ<sub>42</sub> 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 Aβ<sub>42</sub> 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 Aβ<sub>42</sub> fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ<sub>42</sub> removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1<sup>+</sup>-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. <italic>In vivo</italic> studies in GA-immunized or CD115<sup>+</sup>-monocyte-grafted APP<sub>SWE</sub>/PS1<sub>ΔE9</sub>-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our <italic>in vitro</italic> findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ<sub>42</sub> oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.</p>