Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies

Abstract

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.

FIGURE 1

TAR-DNA-binding protein 43 (TDP-43) pathology in Alzheimer disease (AD). Immunohistochemistry with anti-TDP-43 showing neuronal cytoplasmic inclusions in dentate granule cells (A). Note the neuronal intranuclear inclusion (NII) (A; arrow). Cytoplasmic inclusions and small neuritic profiles in entorhinal cortex (B), temporal cortex (C), and frontal cortex (D) in a case with diffuse TDP-43 pathology. Higher magnification of an NII in the frontal cortex is shown (E). An AD case with hippocampal sclerosis shows abundant neuritic pathology in the CA1 region (F). (G–O) Double label immunofluorescence with anti-TDP-43 (G, J, M) and anti-tau (H, K, N). Merged images show cell nuclei stained with 4′6-diamidino-2-phenylindole (I, L, O). Inclusions in the dentate granule cells are either labeled by anti-TDP-43 or anti-tau (G–I). Partial colocalization of tau and TDP-43 signals is observed in neurons in the entorhinal cortex, whereas the neuritic tau pathology is not stained by anti-TDP-43, and 2 TDP-43-positive neuronal inclusions are not labeled by anti-tau (J–L). (M–O) Higher magnification of neurons with partially overlapping (O; arrow) or separate TDP-43- and tau-positive inclusions (O; arrowhead). Scale bars = (A) 50 (A–D, G–L); (E) 25; and (M–O) 20 µm.

FIGURE 2

Pattern of tau and TAR-DNA-binding protein 43 (TDP-43) pathology in CBD. Anti-tau immunohistochemistry reveals characteristic features of corticobasal degeneration with astrocytic plaques, neurofibrillary tangles, and numerous dystrophic neurites in the frontal gray matter (A) and numerous threadlike processes and coiled bodies in the white matter (B). (C) Immunohistochemistry of the same case with anti-TDP-43 showed neuronal cytoplasmic inclusions in dentate granule cells with a single neuronal intranuclear inclusion (C; arrow). In the frontal gray matter, there are several TDP-43-positive threadlike inclusions that are often arranged in annular clusters resembling astrocytic plaques (D). The frontal white matter shows TDP-43-positive threadlike processes and oligodendroglial inclusions (E). Double label immunofluorescence for TDP-43 (F, I) and tau (G, J) with merged images (H, K) shows partial colocalization of most TDP-43-positive threadlike inclusions with tau in the frontal gray matter. A small subset of inclusions is labeled by TDP-43 alone, whereas numerous tau-inclusions are TDP-43 negative (F–H). In the frontal white matter, TDP-43-positive threadlike inclusions partially colocalize with tau. In addition, there are inclusions that are single labeled for either tau or TDP-43 (I–K). Scale bars = (A) 100 (A, B); 50 (D, E); 25 (C; insert in E); 20 (I–K); and 15 µm (F–H).

FIGURE 3

Biochemical analysis of TAR-DNA-binding protein 43 (TDP-43) in Alzheimer disease (AD), corticobasal degeneration (CBD), progressive supalsy (PSP) Pick disease (PiD), and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) cases. Proteins were sequentially extracted from hippocampus (HP) and frontal cortex (FC) of AD cases with diffuse (AD 1), limbic (AD 2, 3, and 5), or no TDP-43 pathology (AD 4), from FC and/or temporal cortex (TC) of CBD cases with (CBD 1 and 4) and without (CBD 2 and 3) TDP-43 pathology. Variable amounts of pathologic TDP-43 bands approximately 25 (*), 45 (†), and high molecular smears (‡) are present in urea samples from AD and CBD cases with TDP-43-positive inclusions by immunohistochemistry (IHC) in the respective brain regions, similar to the distinct pathologic profile of TDP-43 obtained in FTLD-U cases used as positive controls. Pathologic TDP-43 species were not detected in progressive PSP cases 1 to 3 or PiD cases 1 to 3, or in AD (AD 4) and CBD (CBD 2 and 3) cases without detectable TDP-43 pathology by IHC.