Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology.
Initially, trans activation responsive region (TAR)-DNA-binding protein 43 (TDP-43) was considered to be a disease-specific component of ubiquitin-positive and tau-negative inclusions in the brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS); however, it is now widely known that this protein also abnormally accumulates in neurons in other neurodegenerative diseases. On the basis of observation mainly in the medial temporal lobe, TDP-43-immunoreactive neuronal inclusions have been detected in 20-30% of Alzheimer disease (AD) brains. However, it is controversial whether these cases represent a combined disease, that is, mixed AD/FTLD-U. To address this issue, it is necessary to obtain more knowledge on the region-specific distribution of TDP-43 immunoreactivity and also about its relationship to AD common pathology. Here, we describe abnormal TDP-43 immunoreactivity in the medial temporal lobe in 5/16 AD patients (31%). Most of the depositions were cytoplasmic inclusions, mainly located in the subiculum and parahippocampal gyrus and rarely in dentate granular cells of the hippocampus. TDP-43-positive inclusions and senile plaque/neurofibrillary tangle distribution were not always identical, and intracellular colocalizations of TDP-43 and phospho-tau were also infrequent. The cases showing TDP-43-positive inclusions in the medial temporal lobe also showed abnormally highly dense TDP-43 immunoreactivity in the frontal, but not in the parietal and occipital cortices. Intracellularly, TDP-43-positive inclusions were highly ubiquitinated and colocalized with p62 immunoreactivity as well. Our findings suggest that abnormal TDP-43 deposition and AD pathology (formation of senile plaques and neurofibrillary tangles) might occur independently. However, taken together with the results of previous reports, the distribution of TDP-43 immunoreactivity in the hippocampus and frontal cortex in AD appear to be varying. We consider that it is still too early to determine that the TDP-43 accumulation is a part of AD pathology or result from a completely independent pathology.
Department of Neurology, Gunma University Graduate School of Medicine, Gunma, Japan.
Ai
A
Kadokura
Tsuneo
T
Yamazaki
Cynthia A
CA
Lemere
Masamitsu
M
Takatama
Koichi
K
Okamoto
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein