High-resolution brain mapping in ALS: multiplexed insights into TDP-43 aggregation and disease mechanisms 2824

Abstract Description Abnormal protein aggregation is a central pathological feature of neurodegenerative diseases (PMID: 30258241), notably observed in Amyotrophic Lateral Sclerosis (ALS), with 97% of cases presenting TAR DNA-binding protein 43 (TDP-43) aggregation (PMID: 17469116). Cytoplasmic TDP-43 inclusions manifest not only in ALS, but also in various other brain disorders, such as dementia with Lewy bodies, Alzheimer’s disease, and certain forms of frontotemporal dementia (PMID: 33051572). Studies on TDP-43 aggregation in ALS have provided insights into how it drives TDP-43 dysfunction and neurodegeneration; however, a comprehensive understanding of the vulnerable neuronal populations and the cellular interactions behind disease pathogenesis is lacking. Previous single-nucleus data have shown an inflammatory signature in prefrontal cortex of ALS patients. In this study, we leveraged multiplex immunofluorescence (mIF) to build high-resolution maps of the brain of ALS patients through deep cellular, molecular, and pathology readouts integration. We have validated an mIF antibody panel targeting TDP-43, inflammatory biomarkers, and major cell types of the central nervous system on postmortem tissue using the COMET™ platform (PMID: 37813886). The mIF panel enabled simultaneous visualization of the interconnected aspects of ALS pathobiology in spatial context, overcoming previous limitations of traditional protein imaging approaches and allowing an unprecedented view of ALS. Funding Sources Z. Butti is supported by the Milton Safenowitz fellowship; ALS association 25-PDF-745 Topic Categories Neuroimmunology (NEUR)