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

Ann Neurol. 2007 May;61(5):435-45. doi: 10.1002/ana.21154.


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 alpha-synuclein and tau in AD, reflecting a propensity for codeposition of abnormal protein conformers, remains to be determined.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Blotting, Western
  • DNA-Binding Proteins / metabolism*
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology*
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies / pathology
  • Male
  • Microscopy, Confocal
  • Microscopy, Immunoelectron
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Sclerosis
  • Ubiquitin / metabolism


  • DNA-Binding Proteins
  • Ubiquitin