Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease.
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.
Rohn
Troy T
TT
Department of Biology, Boise State University, Boise, ID 83725, USA. trohn@boisestate.edu
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001344:Autopsy; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D007128:Immunoglobulin Fragments; D011994:Recombinant Proteins; D025801:Ubiquitin; D020169:Caspases