Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

Recent studies have revealed the clinical, histological, and pathophysiological characteristics in a group of inflammatory myopathies with selected autoantibodies. We retrospectively compared the clinical manifestations and histological features between 8 anti-mitochondrial (anti-M2) antibody-positive and 33 antibody-negative patients. Patients with anti-M2 antibodies have been previously reported to have delayed diagnostic confirmation and frequent cardiopulmonary complications in comparison to those without the antibodies. In our study, clinical characteristics in patients with the antibodies were as follows: lesser degree of limb muscle weakness and atrophy as well as lymphocytic infiltration in muscle biopsy specimens, and frequent paravertebral muscle atrophy. Anti-M2 antibody appeared to be a biomarker related to not only cardiopulmonary complications, but also characteristic ­distributions of affected muscles.

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aβ production, we performed a gene microarray–based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aβ production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aβ production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3–binding protein (GAL3BP), which suppressed Aβ production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aβ production by directly interacting with APP and thereby inhibiting APP processing by β-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

Intracellular localization of novel human brain carboxypeptidase B (HBCPB) was investigated in human hippocampus, using immunohistochemistry by confocal laser microscopy and biochemical purification of the homogenate by density gradient ultracentrifugation. The former revealed that the majority of HBCPB was expressed in the endoplasmic reticulum, in which the HBCPB-specific C14-module immunoreactivity was colocalized with GRP78 immunoreactivity, a stress 70 heat shock protein specifically expressed in the endoplasmic reticulum. The latter showed that anti-C14-module immunoreactivity and prepro-HBCPB immunoreactivity were both enriched in the microsome fraction, especially in that of the endoplasmic reticulum-density fraction of normal human hippocampal homogenates from various sources. However, HBCPB prepared from human hippocampus showed exopeptidase activity for synthetic beta-amyloid 1-42 peptide, in which Abeta X-42 C-terminus immunoreactivity was decreased in a fashion dose-dependent of the amount of the protease added. These findings indicate that HBCPB, which is expressed in the endoplasmic reticulum of a group of neuronal perikarya, may play an important physiological role in degradation of beta-amyloid 1-42, which is specifically generated in the endoplasmic reticulum of human and rodent neurons and is also regarded as the most pathogenic and aggregatable species among all beta-amyloid peptides.

Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.