Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration.
• The role of non-neuronal cells, particularly microglia, in ALS pathogenesis is not fully understood.
• Previous studies suggested microglia might contribute to neurodegeneration in ALS.

Purpose of the Study:

• To investigate the role of microglia in a mouse model of ALS with reversible human TDP-43 (hTDP-43) pathology.
• To determine if microglia exert neuroprotective or neurodegenerative effects in ALS.
• To explore potential therapeutic strategies targeting microglia.

Main Methods:

• Generation of rNLS8 mice with inducible neuronal hTDP-43 expression.
• Analysis of microglial morphology, proliferation, and gene expression during disease progression and recovery.
• Pharmacological inhibition of microgliosis using PLX3397 (a CSF1R and c-kit inhibitor).
• Assessment of motor function recovery after hTDP-43 suppression.

Main Results:

• Microglia showed subtle changes during active disease but dramatically proliferated and activated upon suppression of hTDP-43.
• Reactive microglia were observed to clear neuronal hTDP-43 aggregates.
• Blocking microgliosis during the recovery phase impaired motor function recovery in rNLS8 mice.
• These findings indicate a crucial neuroprotective role for reactive microglia.

Conclusions:

• Reactive microglia exert significant neuroprotective functions in this ALS mouse model.
• Microglial clearance of toxic TDP-43 pathology is vital for neuronal recovery.
• Targeting microglial activation represents a promising therapeutic strategy for ALS.