A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change

Topic: Brain proteins, microglia and lab models

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). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was 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 immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.

@article{zheng2026-42562773,
  author  = {Zheng, Xiaojing and Zhang, Ning and Wang, Lixia and Zhao, Hongjuan and Liu, ChengGang and Wang, Jiayu and Zhao, Wanli and Zhao, Junli and others},
  title   = {{A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change}},
  journal = {Journal of Neuropathology \& Experimental Neurology},
  year    = {2026},
  doi     = {10.1093/jnen/nlag085},
  pmid    = {42562773},
  url     = {https://doi.org/10.1093/jnen/nlag085}
}

Key findings

• 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 immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology.
• These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.

Why it matters

This autopsy study compared a phosphorylation-independent antibody with a phospho-specific antibody for detecting TDP-43 pathology across frontotemporal lobar degeneration, ALS and LATE-NC, including in Alzheimer's disease neuropathologic change. The findings suggest the new antibody may be a complementary tool for subtype refinement and biomarker development, but this is laboratory and autopsy work, not a treatment study.

New to this subject? Start with our plain-English guide: Treatments →

Study details

• Evidence strengthModerate

Read the original

• DOI: 10.1093/jnen/nlag085
• PubMed: 42562773
• Original source →
• Free full text: Journal of Neuropathology & Experimental Neurology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 16.

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta neuropathologica · 2007-06-20 · usefulness score 59/100 · Getting a diagnosis
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD) Acta neuropathologica · 2014-01-10 · usefulness score 57/100 · Caregiving
• Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease Archives of neurology · 2001-11-01 · usefulness score 56/100 · Getting a diagnosis
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100 · Lewy body dementia
• Updated TDP-43 in Alzheimer's disease staging scheme Acta neuropathologica · 2016-01-25 · usefulness score 54/100 · Lewy body dementia

Related studies in Treatments

• Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients Nature communications · 2014-09-12 · usefulness score 40/100
• Pharmacologic Treatments for Dementia and the Risk of Developing Age-Related Macular Degeneration JAMA network open · 2024-10-01 · usefulness score 75/100
• Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration Proceedings of the National Academy of Sciences of the United States of America · 2011-06-20 · usefulness score 36/100
• The efficacy and safety of anti-amyloid monoclonal antibody versus acetylcholinesterase inhibitor with an in-depth analysis across genotypes and disease stages: a systematic review and meta-analysis The journal of prevention of Alzheimer's disease · 2025-05-01 · usefulness score 83/100
• Rates of cognitive change in Alzheimer disease: observations across a decade of placebo-controlled clinical trials with donepezil Alzheimer disease and associated disorders · 2009-10-01 · usefulness score 56/100
• Alzheimer's Disease Diagnosis and Management in the Age of Amyloid Monoclonal Antibodies The Medical clinics of North America · 2024-11-19 · usefulness score 43/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Targeting the miR‐96‐5p/Cathepsin B Pathway to Alleviate Neuron‐Derived Neuroinflammation in Alzheimer's Disease MedComm · 2025-09-01 · usefulness score 40/100 · Inflammation and the immune system
• FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons Nature communications · 2017-03-30 · usefulness score 54/100 · Lewy body dementia
• Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy Neurochemistry international · 2010-03-27 · usefulness score 38/100 · Biomarkers

Similar studies

• Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies 2009 · Brain tissue and pathology
• TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions 2007 · Lewy body dementia
• Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation 2022 · Brain tissue and pathology
• TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration 2008 · Disease mechanisms
• A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD 2025 · Brain tissue and pathology
• Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration 2025 · Brain tissue and pathology

More on Treatments

• A review that covers this ground Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Anti-Amyloid Beta Therapy The journal of prevention of Alzheimer's disease · 2022-01-01 · usefulness score 40/100
• Newest in this subject Opposing Regulation of Tau Condensation by Phosphorylation Levels and Molecular Chaperone Interactions bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Natural Sesquiterpenoids from Laggera pterodonta as bioactive Acetylcholinesterase Inhibitors: Insights from DFT, Molecular Docking, and ADMET Profiling Research Square · 2026-10-20 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Treatments →