ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation

Area of Science:

• Neuroimmunology
• Molecular Biology
• Cellular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease.
• Transactive response DNA binding protein (TDP-43) pathology is present in ~90% of ALS patients.
• Immune dysfunction is increasingly recognized as a factor in ALS progression.

Purpose of the Study:

• To investigate whether TDP-43 aggregates elicit immune responses.
• To elucidate the mechanism by which TDP-43 aggregates interact with immune cells.
• To explore the immunological consequences of TDP-43 aggregation in ALS.

Main Methods:

• Utilized a multiplex imaging platform.
• Analyzed antigen-presenting cell populations for TDP-43 aggregate internalization.
• Assessed innate and adaptive immune cell activation and infiltration in ALS white matter.

Main Results:

• TDP-43 aggregates are internalized by antigen-presenting cells, leading to vesicle rupture.
• TDP-43 aggregates drive innate and adaptive immune cell activation via antigen presentation.
• Activated microglia/macrophages, CD8 T cells, and MHC expression are enriched in ALS white matter, correlating with TDP-43 pathology.

Conclusions:

• TDP-43 aggregates induce a significant immune response.
• This study reveals a novel immunological pathway in ALS pathogenesis.
• Understanding this cellular response to TDP-43 aggregates offers new insights into ALS progression.