The Role of TDP-43 in Alzheimer’s Disease

Chang, Xiaolong; Tan, Meng-Shan; Tan, Lan; Yu, Jin‐Tai

doi:10.1007/s12035-015-9264-5

Cited by 69 publications

(46 citation statements)

References 92 publications

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“…6 and Table 2). Our results are in accordance with previous reports which indicate that, in advanced AD cases, TDP43 positive cytoplasmic inclusions are found in around 75% of the cases [38]. Finally, we have measured the number of A␤ plaques in CA1 region for each case which, as expected, correlates with the severity of the disease (see Supplementary Fig.…”

Section: At100/ps396 Ratio and Braak Stagesupporting

confidence: 92%

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Regalado-Reyes

Furcila

Hernández

et al. 2019

JAD

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Despite extensive studies regarding tau phosphorylation progression in both human Alzheimer's disease cases and animal models, the molecular and structural changes responsible for neurofibrillary tangle development are still not well understood. Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI. Our results indicate that the AT100/pS396 ratio decreases in CA1 in accordance with the severity of the disease, along with its colocalization. We therefore propose the AT100/pS396 ratio as a new tool to analyze the tau pathology progression. Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer's disease.

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Section: At100/ps396 Ratio and Braak Stagesupporting

confidence: 92%

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Regalado-Reyes

Furcila

Hernández

et al. 2019

JAD

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“…Conversely, approximately 40% of DLB patients have AD pathology as determined by their CSF-biomarker profile [199]. Furthermore, up to half of AD patients harbour transactive response DNA-binding protein 43 (TDP-43) inclusions that are characteristic of frontotemporal lobar degeneration (FTLD) and sporadic amyotrophic lateral sclerosis (ALS) [7, 50, 159]. Amylin deposits, which are found in the pancreas of most patients with type 2 diabetes mellitus, have also been found in AD (and type 2 diabetes) brains [157].…”

Section: Alzheimer’s Disease Pathological Mechanismsmentioning

confidence: 99%

“…Under pathophysiological conditions, TDP-43 accumulates in the cytoplasm and is hyperphosphorylated and/or ubiquitinated, and this is characteristic of the cytoplasmic inclusions observed in ALS and in many cases of FTLD [51, 265]. TDP-43 pathology is also detected in 20–50% of AD patients [7, 50, 159], and appears to be associated with greater brain atrophy, memory loss, and cognitive impairment [50, 163]. Studies suggest that TDP-43 pathology can be triggered by Aβ peptides, and that TDP-43 contributes to neuroinflammation and may have a role in mitochondrial and neural dysfunction [50].…”

Section: Tdp-43 Pathologymentioning

confidence: 99%

“…TDP-43 pathology is also detected in 20–50% of AD patients [7, 50, 159], and appears to be associated with greater brain atrophy, memory loss, and cognitive impairment [50, 163]. Studies suggest that TDP-43 pathology can be triggered by Aβ peptides, and that TDP-43 contributes to neuroinflammation and may have a role in mitochondrial and neural dysfunction [50]. …”

Section: Tdp-43 Pathologymentioning

confidence: 99%

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Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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“…Since TDP-43based neuropathology is present in ~50% of FTLD and ~97% of ALS cases (16), TDP-43 represents a molecular link connecting these neurodegenerative diseases as a clinicopathological spectrum of the proteinopathies (14,(17)(18)(19) . It was also pointed out that TDP-43 may contribute to the pathogenesis of Alzheimer's disease (AD) via both β-amyloid (Aβ)dependent and Aβ-independent pathways (20). Furthermore, TDP-43 abnormalities have also been associated with traumatic brain injury (chronic traumatic encephalopathy) in both pre-clinical and clinical studies (7) and observed in cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease and some other maladies (21).…”

Section: Introductionmentioning

confidence: 99%

Granulins modulate liquid-liquid phase separation and aggregation of TDP-43 C-terminal domain

Bhopatkar

Uversky

Rangachari

2019

Preprint

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Tar DNA binding protein (TDP-43) has emerged as a key player in many neurodegenerative pathologies including frontotemporal lobar degeneration (FTLD) and amyotropic lateral sclerosis (ALS). Important hallmarks of FTLD and ALS are the toxic cytoplasmic inclusions of Cterminal fragments of TDP-43 (TDP-43CTD), which are formed upon proteolytic cleavage of fulllength TDP-43 in the nucleus and subsequent transport to the cytoplasm. TDP-43CTD is also known to form stress granules (SGs) by coacervating with RNA in cytoplasm under stress conditions and are believed to be involved in modulating the pathologies. Among other factors affecting these pathologies, the pleiotropic protein called progranulin (PGRN) has gained significant attention lately. The haploinsufficiency of PGRN, caused by autosomal dominant mutations in GRN gene, results in its loss-of-function linked to FTLD and ALS. But precisely how the protein contributes to the pathology remains unknown. Recently, cleavage to GRNs were observed to be a significant part of FTLD and ALS progression with specific GRNs exacerbating TDP-43-induced toxicity in C.elegans. In this report, we show that GRNs -3 and -5 directly interact with TDP-43CTD to modulate latter's aggregation or stress granule formation in disparate ways in vitro. These results constitute the first observation of direct interaction between GRNs and TDP-43 and suggest a mechanism by which the loss of PGRN function could lead to FTLD and ALS.

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The Role of TDP-43 in Alzheimer’s Disease

Cited by 69 publications

References 92 publications

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Current state of Alzheimer’s fluid biomarkers

Granulins modulate liquid-liquid phase separation and aggregation of TDP-43 C-terminal domain

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