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

TLDR

It is unclear whether TDP‑43 pathology in Alzheimer’s disease reflects concomitant FTLD‑U or merely co‑localization of abnormal proteins. The study sought to quantify FTLD‑U frequency in hippocampal sclerosis and Alzheimer’s disease via TDP‑43 immunohistochemistry. They screened 21 hippocampal sclerosis and 74 Alzheimer’s disease cases for FTLD‑U with TDP‑43 staining, confirmed findings in 93 additional AD cases, and assessed antibody specificity by confocal, electron microscopy, and biochemistry. TDP‑43 immunoreactivity was detected in 71 % of hippocampal sclerosis and 23 % of Alzheimer’s disease cases, with inclusions distinct from tau tangles and associated with granular/filamentous cytosolic material; a higher‑molecular‑weight band appeared in TDP‑43‑positive AD cases, indicating that up to 20 % of AD and over 70 % of hippocampal sclerosis cases show FTLD‑U–like pathology. Published in Annals of Neurology, 2007;61:435–445.

Abstract

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. Ann Neurol 2007;61:435–445