Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease

Brain Res. 2008 Sep 4;1228:189-98. doi: 10.1016/j.brainres.2008.06.094. Epub 2008 Jul 2.

Abstract

The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer's disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP- 43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of HeLa cells with staurosporine. Application of this antibody in postmortem brain sections indicated the presence of caspase-cleaved TDP-43 in Hirano bodies, tangles, reactive astrocytes and neuritic plaques of the AD brain. Caspase-cleaved TDP-43 also co-localized with ubiquitin labeled neurons as well as dystrophic neurites within plaque regions. These results suggest that caspase-cleaved TDP-43 is a major pathological finding in AD and may contribute to the neurodegeneration associated with this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Autopsy
  • Blotting, Western
  • Brain / metabolism*
  • Brain / pathology
  • Caspases / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Immunoglobulin Fragments / genetics
  • Immunoglobulin Fragments / metabolism
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Mice
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Recombinant Proteins / metabolism
  • Ubiquitin / metabolism

Substances

  • DNA-Binding Proteins
  • Immunoglobulin Fragments
  • Recombinant Proteins
  • Ubiquitin
  • Caspases