TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis

Wang, Jing; Yan, Ke; Wu, Zhiqiang; Zheng, Chuanyi; Xu, Ran; Chen, Lihua; Wen, Zhongmin; Zhao, Haoyu

doi:10.1016/j.neulet.2014.03.075

Cited by 11 publications

(12 citation statements)

References 31 publications

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“…These data are shown in Figure S2 in Supplementary Material. Wang et al (36) demonstrated that AICD binds to and co-localizes with TDP-43 in the nucleus of cultured HEK293 cells. In our study, we neither found a significant correlation between AICD expression and cytoplasmic pho-TDP-43 expression nor did we observe co-localization between the two (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

et al. 2016

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BackgroundSeveral findings suggest that the amyloid precursor protein (APP) and the amyloid cascade may play a role in motor neuron disease (MND).ObjectiveConsidering that dementia is one of the most frequent non-motor symptoms in amyotrophic lateral sclerosis (ALS) and that hippocampus is one of the brain areas with greater presence of amyloid-related changes in neurodegenerative diseases, our aim was to analyze the molecular markers of the amyloid cascade of APP in pathology studies of the hippocampus of autopsied patients with ALS and ALS–frontotemporal dementia (FTD).MethodsWe included nine patients with MND and four controls. Immunohistochemical studies and confocal microscopy were used to analyze the expression of APP, TDP-43, pho-TDP-43, Aβ, APP intracellular cytoplasmatic domain (AICD) peptide, Fe65 protein, and pho-TAU in the hippocampus of seven patients with ALS, two patients with ALS–FTD, and four controls. These findings were correlated with clinical data.ResultsPatients displayed increased expression of APP and Aβ peptide. The latter was correlated with cytoplasmic pho-TDP-43 expression. We also found decreased Fe65 expression. A parallel increase in AICD expression was not found. Patients showed increased expression of pho-TAU in the hippocampus. Findings were similar in patients with ALS and those with ALS–FTD, though more marked in the latter group.ConclusionPost-mortem analyses showed that the amyloid cascade is activated in the hippocampus of patients with MND and correlated with cytoplasmic pho-TDP-43 expression. The number of intracellular or extracellular aggregates of Aβ peptides was not significant.

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Section: Resultsmentioning

confidence: 99%

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

et al. 2016

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“…It is important for future study even though low specificity limited those biomarkers as auxiliary function in disease diagnosis. Interestingly, a study suggests that CSF phospho-tau181/ total-tau (p/t-tau) ratio is significantly reduced in FTLD-TDP relative to FTLD-tau [47]; whether this ratio is useful to speculate the causing proteinopathy needs to be further elucidated.…”

Section: Csf Tdp-43 In Admentioning

confidence: 99%

“…Accumulation of amyloid results in declined solubility of cytosolic proteins such as tau, α-synuclein, and TDP-43 [51]. The cleavage of APP by β-secretase and γ-secretase could generate Aβ and intracellular domain of APP (AICD), respectively [47]. Notably, AICD has been demonstrated to have the ability to cause AD pathology independent of Aβ, TDP-43 co-localize with AICD in nuclear, functioning as an enhancer in upregulating of P53 messenger RNA (mRNA), and further promotes AICD-induced apoptosis.…”

Section: Aβ-dependent Role Of Tdp-43 In Admentioning

confidence: 99%

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The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

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The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.

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“…42,43 Of particular interest is the technology growth curve for the transactive response DNA-binding protein of 43 kDa (TDP-43), a protein first identified for its association with amyotrophic lateral sclerosis and more recently associated with AD. [44][45][46] Growth of publications related to TDP-43 could not be modeled with the sigmoid function. Closer analysis suggests that this technology is still in the exponential, growing stage of the growth cycle and has not yet approached the established stage.…”

Section: Modeling Technologies For Ad Discoverymentioning

confidence: 99%

Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity

Beierlein

McNamee

Walsh

et al. 2015

Clinical Therapeutics

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This analysis suggests that AD drug discovery has followed a predictable pattern of innovation in which technological maturity is an important determinant of success in development. Quantitative analysis indicates that the lag in emergence of new products, and the much-heralded clinical failures of recent years, should be viewed in the context of the ongoing maturation of AD-related technologies. Although these technologies were not sufficiently mature to generate successful products a decade ago, they may be now. Analytical models of translational science can inform basic and clinical research results as well as strategic development of new therapeutic products.

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TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis

Cited by 11 publications

References 31 publications

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

The Role of TDP-43 in Alzheimer’s Disease

Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity

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