C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease
Angela Gomez-Arboledas1, Maria I Fonseca1, Enikö Kramar2
1Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA.
Introduction:
Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.
Methods:
A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD.
Results:
Genetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP).
Discussion:
Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.
Highlights:
C5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease.
Insights
Inhibiting C5aR1 in mouse models of Alzheimer's disease (AD) partially reverses synaptic loss and improves cognitive function, suggesting C5aR1 as a therapeutic target for AD.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Synaptic loss is a key feature of Alzheimer's disease (AD), strongly linked to cognitive decline.
- Complement-mediated synaptic pruning by microglia and astrocytes contributes to this excessive synapse loss in AD.
Purpose of the Study:
- To investigate the impact of inhibiting the C5a receptor 1 (C5aR1) on microglial and astroglial synaptic pruning in AD mouse models.
- To evaluate the therapeutic potential of targeting the C5a-C5aR1 pathway in Alzheimer's disease.
Main Methods:
- Utilized super-resolution, confocal, and 3D image reconstruction techniques.
- Assessed the effects of genetic C5aR1 ablation and pharmacological C5aR1 inhibition.
- Studied the Arctic48 and Tg2576 mouse models of AD.
Main Results:
- Genetic or pharmacological inhibition of C5aR1 partially rescued excessive pre-synaptic pruning and synaptic loss in an age- and region-dependent manner.
- These improvements correlated with enhanced long-term potentiation (LTP), indicating restored synaptic function.
- C5aR1 inhibition, including the antagonist PMX205, mitigated synaptic marker loss (VGlut1) in the Tg2576 model.
Conclusions:
- Suppression of C5a-C5aR1 signaling offers a beneficial reduction in excessive synaptic pruning.
- Targeting C5aR1 presents a promising therapeutic strategy for managing Alzheimer's disease and its associated cognitive deficits.
