Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to A oligomers accumulation

Antonella Caccamo, Andrea Magrí, Salvatore Oddo

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background. Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with A and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Results. Here we show that levels of TDP-43 and its ∼35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of A and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble A oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing A42production restores the levels of TDP-43 and its ∼35 kDa C-terminal fragment to control levels. Conclusions. These data suggest a possible relation between A oligomers and TDP-43.

Original languageEnglish (US)
Article number51
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

DNA-Binding Proteins
Alzheimer Disease
Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Cytoplasm
Animal Models
Pathology

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to A oligomers accumulation. / Caccamo, Antonella; Magrí, Andrea; Oddo, Salvatore.

In: Molecular Neurodegeneration, Vol. 5, No. 1, 51, 2010.

Research output: Contribution to journalArticle

@article{a233ed49375e4c3595d840ba618da578,
title = "Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to A oligomers accumulation",
abstract = "Background. Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30{\%} of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with A and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Results. Here we show that levels of TDP-43 and its ∼35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of A and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble A oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing A42production restores the levels of TDP-43 and its ∼35 kDa C-terminal fragment to control levels. Conclusions. These data suggest a possible relation between A oligomers and TDP-43.",
author = "Antonella Caccamo and Andrea Magr{\'i} and Salvatore Oddo",
year = "2010",
doi = "10.1186/1750-1326-5-51",
language = "English (US)",
volume = "5",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to A oligomers accumulation

AU - Caccamo, Antonella

AU - Magrí, Andrea

AU - Oddo, Salvatore

PY - 2010

Y1 - 2010

N2 - Background. Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with A and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Results. Here we show that levels of TDP-43 and its ∼35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of A and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble A oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing A42production restores the levels of TDP-43 and its ∼35 kDa C-terminal fragment to control levels. Conclusions. These data suggest a possible relation between A oligomers and TDP-43.

AB - Background. Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with A and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated. Results. Here we show that levels of TDP-43 and its ∼35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of A and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble A oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing A42production restores the levels of TDP-43 and its ∼35 kDa C-terminal fragment to control levels. Conclusions. These data suggest a possible relation between A oligomers and TDP-43.

UR - http://www.scopus.com/inward/record.url?scp=78149318021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78149318021&partnerID=8YFLogxK

U2 - 10.1186/1750-1326-5-51

DO - 10.1186/1750-1326-5-51

M3 - Article

VL - 5

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 51

ER -