IntroductionThe transactivation response element DNA-binding protein 43 kDa (TDP-43) is a major component of the ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration and sporadic amyotrophic lateral sclerosis (ALS). TDP-43 may accumulate in cases of Alzheimer’s disease (AD), Lewy body disease (LBD), and argyrophilic grain disease (AGD). However, few studies have focused on the incidence and extent of TDP-43 deposition in aging.ResultsWe analyzed 286 consecutive autopsy brains neuropathologically. Of these, 136 brains with pathologically minimal senile changes were designated as control elderly brains (78.5 ± 9.7 y). For comparison, we selected 29 AD, 11 LBD, and 11 AGD patients from this series of autopsy brains. Sections of the hippocampus, amygdala, medulla oblongata, and lumbar spinal cord were immunostained with anti-phosphorylated TDP-43 antibody (PSer409/410). TDP-43 immunoreactive structures were classified into four types: dystrophic neurites (DNs), neuronal or glial cytoplasmic inclusions, and intranuclear inclusions. TDP-43 immunoreactive structures were observed in 55/136 control elderly (40.0 %), 21/29 AD (72.4 %), 8/11 LBD (72.7 %), and 6/11 AGD (54.5 %) brains. TDP-43 immunoreactive structures in control elderly brains were mostly DNs. These DNs were predominantly present in the uncus of the anterior hippocampus over age 65. The frequency of cases with DNs in the amygdala of control elderly brains was less than that of AD, LBD, and AGD brains. The mean age at death was significantly higher in cases with TDP-43 immunoreactive structures than cases without them.ConclusionsIn conclusion, TDP-43 immunoreactive DNs may develop as a consequence of aging processes in the human brain. In particular, the uncus of the anterior hippocampus is an area highly susceptible to TDP-43 accumulation over age 65.

BackgroundLewy body–related α-synucleinopathy (LBAS, the abnormal accumulation of pathologic α-synuclein) is found in the central and peripheral nervous systems, including the spinal cord, dorsal root ganglia, and sympathetic ganglia, of Parkinson’s disease patients. However, few studies have focused on the distribution of LBAS in the spinal cord, primary sensory neurons, and preganglionic sympathetic nerves.ResultsWe analyzed 265 consecutive subjects with LBAS who underwent autopsy at a general geriatric hospital. LBAS in the spinal cord was significantly associated with that in the lower brainstem regions that are directly connected to the spinal cord (i.e., the medullary reticular formation and locus ceruleus), but it was not associated with the olfactory bulb–amygdala system, which is not directly connected to the spinal cord, suggesting that the lower brainstem is a key structure regarding the spread of LBAS to the spinal cord. In the primary sensory neurons, most subjects with LBAS in the dorsal root ganglia had LBAS in the dorsal root, and all subjects with LBAS in the dorsal root also had LBAS in the dorsal horn, suggesting that LBAS spreads retrogradely from the axonal terminals of the dorsal horn to the somata of the dorsal root ganglia via the dorsal root. In the preganglionic sympathetic nerves, the LBAS in the sympathetic ganglia preceded that in the nucleus of the intermediolateral column of the thoracic cord, suggesting that LBAS spreads retrogradely through the preganglionic sympathetic nerves.ConclusionsLBAS in the spinal cord was associated with the lower regions of the brainstem, but not with the olfactory bulb or amygdala. LBAS may spread centrifugally along the primary sensory neurons, whereas it may spread centripetally along the preganglionic sympathetic nerves.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0236-9) contains supplementary material, which is available to authorized users.

Neuronal intranuclear hyaline inclusion disease (NIHID) is a rare neurodegenerative disorder pathologically characterized by localized neuronal loss, and the presence of eosinophilic intranuclear inclusions in neurons and glial cells. NIHID is a heterogeneous disease entity. It is divided into three clinical subgroups: infantile, juvenile and adult forms. Recently, reports of adult-onset cases have increased. Typical adult-onset NIHID consists of cognitive dysfunction with leukoencephalopathy. This type of adult-onset NIHID can be predicted by characteristic magnetic resonance images, high intensity areas on T2-weighted/fluid-attenuated inversion recovery images and persistent high intensity at the corticomedullary junction in diffusion-weighted images. When clinically suspected, the ante-mortem diagnosis can be made by biopsy. In adult-onset NIHID, nuclear inclusions are found more frequently in glial cells, and moderate to severe white matter degeneration is often associated. Although the underlying pathological mechanisms of NIHID are largely unknown, abnormal intranuclear accumulations of proteins and/or dysfunction of protein degradation systems might be related to the pathogenesis. To further clarify the characteristics of this disease entity, biological and pathological analysis of the patients is indispensable. As this disease entity becomes better known, diagnosed cases are expected to increase. Adult-onset NIHID might not be as extremely rare as previously thought.

s from another snake venom were found to exhibit similar receptor binding properties to KDR-bp. This is the first report to demonstrate that an exogenous factor antagonizes VEGF and its receptor system. Our observation offers further insight into the as yet unknown molecular mechanism of myotoxic activity of snake venom Lys 49 PLA2s. Furthermore, KDR-bp would make a valuable tool for studying the structure and function of KDR, such as that expressed on skeletal muscle cells.

Long non-coding RNAs (lncRNAs) have been reported to be involved in the physiological and pathological processes of tumor pathogenesis, including epithelial-mesenchymal transition (EMT). However, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance is a major challenge in the treatment of advanced and recurrent EGFR-mutant lung adenocarcinoma. An increased understanding of the underlying mechanisms would aid in the development of effective therapeutic strategies against EGFR-TKI resistance, strategies which are urgently required for clinical therapy. In this study, long non-coding RNA LINC00460 was identified as a novel marker of a poor response to EGFR-TKI and prognosis. In lung cancer cells, LINC00460 promoted EGFR-TKI resistance as a competitive decoy for miR-149-5p, thereby facilitating interleukin (IL)-6 expression and inducing EMT-like phenotypes. The knockdown or knockout of LINC00460 in gefitinib-resistant non-small cell lung cancer cells restored the response to EGFR-TKI. In addition, as compared with patients with a low LINC00460 expression in tumors, those with a high LINC00460 expression had a significantly shorter progression-free survival following gefitinib therapy, and a shorter overall survival. Therefore, LINC00460 may be a predictor of and potential therapeutic target for EGFR-TKI resistance.