Regional distribution of TDP‐43 inclusions in Alzheimer disease (AD) brains: Their relation to AD common pathology

<jats:p>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.</jats:p>