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TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss
Rosa C Paolicelli1, Ali Jawaid2, Christopher M Henstridge3
1Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland.
Abstract:
Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
Insights
Microglia regulate brain health, but their overactivity may cause synapse loss. Research shows TDP-43 in microglia impacts amyloid clearance and synapse integrity, suggesting a role in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are key immune cells in the central nervous system, essential for synaptic pruning, homeostasis, and clearing protein aggregates.
- Dysfunctional microglial activity, particularly excessive phagocytosis, is increasingly implicated in neurodegenerative conditions.
Purpose of the Study:
- To investigate if heightened microglial phagocytic activity, while clearing amyloid, can paradoxically lead to pathological synapse loss.
- To explore the role of TDP-43 in regulating microglial phagocytosis and its impact on neurodegeneration.
Main Methods:
- Utilized a mouse model of Alzheimer's disease (AD) with genetic modifications in microglial TDP-43 expression.
- Analyzed amyloid load and synapse integrity in these mice.
- Examined clinical data from human cases with TDP-43 pathology.
Main Results:
- Mice lacking TDP-43 in microglia showed reduced amyloid burden but significant synapse loss, independent of amyloid.
- Human TDP-43 pathology cases exhibited lower prevalence of AD and reduced amyloid pathology compared to controls.
Conclusions:
- TDP-43 is a critical regulator of microglial phagocytosis, influencing both amyloid clearance and synapse maintenance.
- Dysfunctional microglia, potentially driven by altered TDP-43 function, may contribute causally to neurodegenerative disorders and cognitive decline.
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