Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD

• Published in: Acta neuropathologica communications Vol. 12; no. 1; pp. 156 - 14
• Main Authors: Chevalier, Elodie, Audrain, Mickael, Ratnam, Monisha, Ollier, Romain, Fuchs, Aline, Piorkowska, Kasia, Pfeifer, Andrea, Kosco-Vilbois, Marie, Seredenina, Tamara, Afroz, Tariq
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.10.2024; BioMed Central; BMC
• Subjects: ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies, Monoclonal - pharmacology; Disease Models, Animal; DNA-Binding Proteins - metabolism; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Humans; Immunotherapy; Mice; Mice, Transgenic; Monoclonal antibodies; Neuropathology; Pathomechanism; Proteases; Protein binding; Spreading; TDP-43; Neuropathology; Immunotherapy; Pathomechanism; Spreading; TDP-43; FTD; ALS
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-024-01867-z

Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.