Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36-56%) and in DLB (53-60%) than previously reported. Of the TDP-43-positive cases, about 20-30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and alpha-synuclein.
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A panel of radiochemicals has enabled in-vivo positron emission tomography (PET) of tau pathologies in Alzheimer′s disease (AD), while sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In-vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant PSP tau topologies. Notably, the in-vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of autopsied and biopsied brains derived from Pick′s disease, PSP and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on the neuropathological basis.
Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.
Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.
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