Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer'S-Related A Beta(42) Oligomers And Protect Synapses

Impaired synaptic integrity and function due to accumulation of amyloid beta-protein (A beta(42)) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of A beta(42) 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 Ab-phagocytic macrophages. We found that cortical neurons were more susceptible to A beta(42) 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 A beta(42) fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased A beta(42) 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(Delta E9)-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 A beta(42) oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.