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.
Highlights
Alzheimer’s disease (AD) is a progressive, incurable and fatal neurodegenerative disorder and the most frequent cause of senile dementia [1, 2]
We indicated that synaptotoxicity was not elicited by non-aggregating sAβ42 peptides but was dependent on their conformation state; cortical neurons were far more vulnerable to Aβ42 oligomers than to fibrils
We further found that M bone marrow (BM) effectively protect against synaptic loss and neurite retraction caused by Aβ42 fibrils yet provide insufficient protection against oligomers
Summary
Alzheimer’s disease (AD) is a progressive, incurable and fatal neurodegenerative disorder and the most frequent cause of senile dementia [1, 2]. Growing evidence demonstrates the detrimental effects of Aβ42 oligomers on synaptic plasticity, spine morphology and density [13, 23], axonal transport [24,25,26], and cognition [8, 15, 17, 22, 27,28,29]. These findings incentivize strategies that eradicate Aβ42 oligomers in order to preserve synapses and cognitive function [30,31,32,33,34]
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