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Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses
Songlin Li1,2,3, Eric Y Hayden4, Veronica J Garcia5,6
1Institute of Neuroscience and Chemistry, Wenzhou University, Wenzhou, China.
Abstract:
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 APPSWE/PS1ΔE9-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.
Insights
Activated macrophages clear amyloid-beta (Aβ) oligomers and protect synapses, offering a potential treatment for Alzheimer's disease (AD). Immune activation enhances macrophage efficacy in clearing toxic Aβ species and preserving synaptic integrity.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Amyloid beta (Aβ) oligomers impair synaptic function, contributing to Alzheimer's disease (AD) cognitive decline.
- The role of Aβ oligomers in synaptotoxicity and the capacity of peripheral immune cells to protect synapses are not fully understood.
- The metastable nature of Aβ oligomers complicates their study.
Purpose of the Study:
- To investigate the differential effects of stabilized Aβ oligomers versus fibrils on neuronal synapses.
- To determine the protective capacity of macrophages against Aβ-induced synaptotoxicity.
- To elucidate the mechanisms by which macrophages clear Aβ oligomers and fibrils, and how immune activation modulates this process.
Main Methods:
- Photo-induced cross-linking stabilized pure Aβ oligomers for comparative analysis with fibrils.
- Co-culture systems of cortical neurons and bone marrow-derived macrophages were used to assess synaptic protection.
- In vitro and in vivo studies in transgenic AD mouse models (APPSWE/PS1ΔE9) involving glatiramer acetate (GA) immunization or monocyte grafting were performed.
Main Results:
- Cortical neurons exhibited greater susceptibility to Aβ42 oligomers than fibrils, leading to neuritic retraction, functional alterations, and loss of excitatory synapses (VGluT1/PSD95).
- Macrophages protected synapses from Aβ42 fibrils; immune activation with glatiramer acetate (GA) further enhanced protection against oligomers.
- GA-stimulated macrophages cleared Aβ42 more effectively via distinct pathways: fibrils through intracellular proteolysis (CD36/EEA1) and oligomers via extracellular degradation (MMP-9).
- In vivo studies confirmed macrophage-mediated synaptic preservation in GA-immunized or monocyte-grafted AD mice.
Conclusions:
- Activated macrophages effectively clear toxic Aβ42 oligomers and preserve VGluT1/PSD95 synapses.
- Immune modulation strategies targeting macrophages represent a promising therapeutic approach for Alzheimer's disease.
- Understanding Aβ oligomer clearance mechanisms by immune cells provides a rationale for developing novel AD treatments.
