Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and Down syndrome

Abstract

Objective: To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present.

Design: Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS.

Results: We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43-positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia.

Conclusions: Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease.

Figure 1

Photomicrographs of transactive response DNA-binding protein 43 (TDP-43) pathology in the brains of patients with familial Alzheimer disease (FAD) and Down syndrome (DS). A, The TDP-43 inclusions in the amygdala at medium power magnification (original magnification ×20) are shown in a participant with Down syndrome (patient 11). Multiple neurons in the amygdala show immunoreactivity for the phosphorylation-specific TDP-43 monoclonal antibody. B–D, Higher-power magnification (original magnification ×60) of neuronal cytoplasmic staining in amygdala neurons was performed for patients withDS (B, patient 11), PS-1–positive FAD (C, patient 44), andPS-2–positive FAD (patient 45). In all participants, there is intense TDP-43 immunoreactivity in aggregates that extended throughout the cytoplasm. The appearance is similar in PS-1–positive FAD, PS-2–positive FAD, and DS.

Figure 2

Photomicrograph of transactive response DNA-binding protein 43 (TDP-43) immunostaining of neuropathological features in patients with familial Alzheimer disease and Down syndrome using monoclonal antibody 1D3. A, In patient 11, TDP-43–positive threadlike structures are demonstrated in the neuropil. B, Granules in granulovacuolar degeneration (GVD) are immunoreactive to TDP-43 (patient 4). C, Diffuse and granular cytoplasmic staining for TDP-43 is shown in dentate granule cells (patient 11). However, none of the other TDP antibodies produced similar GVD or granular staining, so we infer that the granular and GVD staining seen here with the 1D3 monoclonal antibody does not reflect the presence of TDP-43 itself in these structures. Original magnification is ×60 for all images.