TDP-43 in aging and Alzheimer's disease - a review

Abstract

Transactive response DNA-binding protein of 43 kDa (TDP-43), an RNA and DNA binding protein involved in transcriptional repression, RNA splicing and RNA metabolism during the stress response, is the major component of neuronal inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD-TDP. While initially thought to be relatively specific to ALS and FTLD-TDP, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, many associated with tau pathology, including Guam Parkinson dementia complex and Alzheimer's disease (AD). TDP-43 pathology is detected in 25% to 50% of AD cases, especially those with more severe clinical phenotype and greater Alzheimer type pathology, as well as AD cases with hippocampal sclerosis (HS). HS is characterized by selective neuronal loss affecting CA1 sector of the hippocampus, and most cases of HS, with or without AD, have TDP-43 pathology. Whether TDP-43 pathology is merely an incidental finding in AD or actually contributing to the more severe clinical phenotype remains unresolved. Presence of TDP-43 in normal elderly, who are at increased risk for AD, would strengthen the argument that it is not merely a secondary or incidental finding in end stage AD. Limited studies suggest that TDP-43 pathology is infrequent in neurologically normal elderly (3% or less). We provide an overview of what is known about TDP-43 in AD, normal aging and in other disorders and suggest that TDP-43 proteinopathies be considered in two classes - primary and secondary.

Keywords: Alzheimer's disease (AD); amyotrophic lateral sclerosis (ALS); frontotemporal lobar degeneration (FTLD); neurofibrillary tangles (NFT); progranulin; tau; transactive response DNA-binding protein 43 (TDP-43).

Figure 1

TDP-43 immunoreactivity in normals. TDP-43 immunohistochemistry in the amygdala of the positive cases at a 40X magnification. Black arrows indicate pathological TDP-43 inclusions, while blue arrows indicate normal nuclear TDP-43. A. An 83-year-old woman with medial temporal tangles and grains. B. An 81-year-old man with minimal entorhinal tangles.

Figure 2

TDP-43 expression in age-matched AD and control subjects. A. Five age-matched AD and four control brain samples were homogenized and run on a 10-20% Tricine Gel. The membrane was probed with the monoclonal TDP-43 antibody (EnCor Biotechnology, Gainesville, FL). One clean band migrating at the expected molecular weight was observed for all samples. The membrane was stripped and re-probed with the goat polyclonal GAPDH antibody (Santa Cruz, CA) as a loading control. B. Intensities of the signal were quantified using the NIH Image J software. There was no difference in TDP-43 expression between AD and control brain samples, after normalization to GAPDH.