A new biomarker for frontotemporal lobar degeneration with TDP-43 proteinopathy and Alzheimer's disease

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Summary The public health impact of TDP-43 (TAR DNA binding protein of 43 kDa) proteinopathy is estimated to be on the same order of magnitude as that of Alzheimer’s disease (AD). TDP-43 was first associated with frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in patients under 65. TDP-43 was later shown to be present in up to 60% of brains with AD, the most common cause of dementia. TDP-43 pathology is heterogeneous in FTLD-TDP and is associated with multiple dementia syndromes, which complicates FTLD-TDP diagnosis in living patients. These patients, who present with a wide range of associated clinical symptoms, are underserved, as their complex clinicopathologic heterogeneity leads to uncertainty surrounding their diagnosis. A major hurdle in elucidating the clinicopathologic relationships between dementia syndromes and specific markers of FTLD-TDP is the heterogeneous molecular species of the TDP-43 inclusions. More specifically, some TDP-43 species are pathologic, while some are not. Similarly, TDP-43 pathology in AD is heterogeneous, and the AD TDP types’ associations with the different molecular species of TDP-43 and neurodegeneration are unknown. Thus, producing an antibody that is specific for the pathologic TDP-43 species will be crucial for elucidating the clinicopathologic relationship in FTLD-TDP and AD. After screening over 5,000 monoclonal antibody (MAb) clones in our lab, we have successfully produced the novel, home-made MAb #9, which is specific for the pathologic TDP-43 species. This antibody can strongly recognize a 35 kDa TDP-43 species rarely reported in humans and can reveal additional dense TDP-43 inclusions in brain areas showing neurodegeneration. The goals of this study are to elucidate this novel, MAb #9-recognized pathologic TDP-43 species and its association with TDP-43 pathology and neurodegeneration in FTLD-TDP and AD. We hypothesize that MAb #9 binds the previously undescribed TDP-43 species present in unique inclusions that localize to brain regions with local neurodegeneration. We will test this hypothesis via three aims. In Aim 1, we will elucidate the amino acid sequence of this novel MAb#9-detected TDP-43 species using tandem mass spectrometry-based proteomic analysis. In Aims 2 and 3, we will determine the relationships between MAb #9- positive inclusions, pathology types, and local neurodegeneration in FTLD-TDP and AD using immunohistochemical and neuropathological approaches. Findings from this study will significantly improve our understanding of a novel toxic TDP-43 species and its association with pathology and neurodegeneration. The findings will be a key step toward developing a biomarker that can predict the presence of TDP-43 in living FTLD and AD patients. Given that TDP-43 is a potential therapeutic target in treating FTLD and now AD, the knowledge will likely also have a significant impact on future therapies for both diseases.