Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.
Acta Neuropathol Commun
; 12(1): 156, 2024 Oct 03.
Article
in En
| MEDLINE
| ID: mdl-39363348
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Disease Models, Animal
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DNA-Binding Proteins
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Frontotemporal Dementia
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Amyotrophic Lateral Sclerosis
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Antibodies, Monoclonal
Limits:
Animals
/
Humans
Language:
En
Journal:
Acta Neuropathol Commun
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: