TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease

Amador-Ortiz, Catalina; Lin, Wen Lang; Ahmed, Zeshan; Personett, David; Davies, Peter; Duara, Ranjan; Graff‐Radford, Neill R.; Hutton, Michael; Dickson, Dennis W.

doi:10.1002/ana.21154

Cited by 766 publications

(784 citation statements)

References 36 publications

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“…TDP-43 has been discovered in both sporadic and familial AD [46][47][48] , and our seeding results showed that TDP-43 oligomers can interact and influence Ab fibrillization. The increased Ab assembly in the presence of TDP-43 could result from a seeding effect that generates new Ab assemblies such as Ab*56 and larger aggregates or formation of cross-linked TDP-43 and Ab complexes.…”

Section: Discussionmentioning

confidence: 53%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-b to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

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Section: Discussionmentioning

confidence: 53%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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“…TDP-43 is the major component of neuronal inclusions, the histopathological hallmark of both ALS and the most frequent subtypes of frontotemporal dementia (FTD), considered the second most common early-onset dementia, characterized by neuronal loss in the frontal and temporal cortex. 6,7 In fact, cytoplasmic TDP-43 accumulation also represents a secondary pathological feature of other major neurodegenerative diseases, including Alzheimer's disease, 8 Parkinson's disease, 9 and Huntington's disease. 10 Despite increasing evidence suggesting a critical role of TDP-43 in disease progression in these various major neurodegenerative diseases, the pathogenic mechanisms underlying TDP-43 are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

et al. 2017

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Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43 M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43 M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43 M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43 M337V mice. Thus, this study suggests hemizygous TDP-43 M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

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“…Moreover, a 400% increase of GRN expression has been observed in the spinal cord of patients with ALS [Malaspina et al, 2001] and Creutzfeldt-Jakob disease (CJD) [Baker and Manuelidis, 2003], most likely as a result of the activation of microglia. In AD and Lewy-body related diseases, TDP-43 immunoreactivity was also observed [Amador-Ortiz et al, 2007;Nakashima-Yasuda et al, 2007;Higashi et al, 2007]. In addition, FTLD and AD are sometimes difficult to differentiate at diagnosis and their key symptoms can be accompanied by parkinsonism, also occuring in FTLD patients carrying a GRN null mutation Mackenzie, 2007].…”

Section: Introductionmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease

Cited by 766 publications

References 36 publications

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

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