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

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

Research output: Contribution to journalArticle

532 Scopus citations

Abstract

Objective: This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP-43), a putative marker for FTLD-U. Methods: Initially, 21 cases of HpScl associated with a variety of other pathological processes and 74 cases of AD were screened for FTLD-U with TDP-43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP-43 antibodies was assessed using double-immunolabeling confocal microscopy, immunoelectron microscopy, and biochemistry. Results: TDP-43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP-43 and phospho-tau showed that the TDP-43-immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level, TDP-43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases showed a band that migrated at a higher molecular weight than normal TDP-43 that was not present in AD cases without TDP-43 immunoreactivity. Interpretation: These results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD-U. Whether this represents concomitant FTLD-U or is analogous to colocalization of α-synuclein and tau in AD, reflecting a propensity for codeposition of abnormal protein conformers, remains to be determined.

Original languageEnglish (US)
Pages (from-to)435-445
Number of pages11
JournalAnnals of neurology
Volume61
Issue number5
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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