A Phosphorylation-Independent Monoclonal Antibody Improves Detection of TDP-43 Pathology Across FTLD, ALS, and LATE-NC

Abstract

TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD TDP), amyotrophic lateral sclerosis (ALS TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE NC), all of which exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We tested whether a phosphorylation independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) more effectively detects architecture-dependent TDP-43 pathology and whether its signal relates to regional neurodegeneration. We analyzed a multicenter autopsy cohort spanning FTLD TDP types A–C, ALS TDP, and Alzheimer’s disease neuropathologic change (ADNC) with or without LATE NC, comparing MAb No. 9 with the phospho-specific pSer409/410 antibody using matched immunohistochemistry, dual label immunofluorescence, and semiquantitative pathology scoring. MAb No. 9 robustly detected pathological TDP-43 across all diagnostic groups, with markedly enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD TDP types A/B and in ALS TDP, while showing performance equivalent to p409/410 in FTLD TDP type C. In ADNC with stage 3 LATE NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label fluorescence demonstrated strong spatial overlap with p409/410, yet MAb No. 9 additionally highlighted fine punctate pathology not readily detected by phospho-specific staining. Notably, in FTLD TDP type A, MAb No. 9 burden correlated strongly with cortical neurodegeneration, whereas p409/410 showed weaker and variable associations, particularly in severely atrophic cortex. Integrating recent cryo-EM data, these findings support a model in which filament architecture governs C-terminal epitope accessibility, positioning MAb No. 9 as a complementary tool for subtype refinement, clinicopathologic correlation, and translational biomarker development in TDP-43 proteinopathies.