Decrease in p3-Alcb37 and p3-Alcb40, products of Alcadein b generated by g-secretase cleavages, in aged monkeys and patients with Alzheimer’s disease

Introduction Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer\u27s disease (AD) contributes for the development of novel therapy and/or drug targets. Methods We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results In monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. Discussion Aging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD

Decrease in p3-Alcb37 and p3-Alcb40, products of Alcadein b generated by g-secretase cleavages, in aged monkeys and patients with Alzheimer’s disease

Introduction Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer\u27s disease (AD) contributes for the development of novel therapy and/or drug targets. Methods We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results In monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. Discussion Aging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD

On the top of ARB N/L type Ca channel blocker leads to less elevation of aldosterone

Synopsis The activation of the renin-angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan + amlodipine compared with valsartan + cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132 + − 10/76 + − 10 compared with 131 + − 10/77 + − 9, P = 0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41 + − 2.67 compared with 2.00 + − 1.50 P = 0.20, PAC (pg/ml): 77.3 + − 31.0 compared with 67.4 + − 24.8, P < 0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9 + − 216.1 compared with 73.9 + − 122.2, P < 0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine

Intracellular Trafficking of the Amyloid β-Protein Precursor (APP) Regulated by Novel Function of X11-Like

Background: Amyloid beta (A beta), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid beta-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by alpha- or beta-, and gamma-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of A beta lowers. X11L expresses another function in the regulation of intracellular APP trafficking. Methodology: In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP. Conclusions: X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Ab generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways

Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity

Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disorder that primarily affects motor neurons. Dominant mutations in the RNA binding protein Fused in Sarcoma (FUS) have been identified as causative factors of ALS. Mutation, R495X, results in a premature stop codon and induces an aggressive disease phenotype by a largely unknown process. Here, we employ CLIP-Seq, RNA-Seq and Ribo-Seq in cultured neurons expressing R495X or wild-type FUS to identify the mutation effects on the FUS targetome and on the neuronal transcriptome at the expression and translation level, simultaneously. We report that, unlike wild-type FUS that binds on precursor mRNAs (pre-mRNAs), R495X binds mature mRNAs in the cytoplasm. R495X has a moderate effect on target mRNA expression and its binding induces only modest expression changes. In contrast, we find that R495X controls the translation of genes that are associated with mitochondria function and results in significant reduction of mitochondrial size. Importantly, we show that introduction of the 4FL mutation that alters binding of R495X to RNA, partially abrogates R495X-induced effects on mRNA translation, mitochondrial size and neurotoxicity. Our findings uncover a novel RNA-mediated pathway of FUS R495X-induced neurotoxicity that affects mitochondria morphology and provide insight to previous studies associating mitochondria dysfunction to ALS

Phylogeny of the Drosophila immigrans species group (Diptera : Drosophilidae) based on Adh and Gpdh sequences

The immigrans species group in the Drosophilinae is one of the representative species groups of Drosophila in East Asia. Although this group constitutes a significant part of the drosophilid fauna in the Old World, only a few species have been analyzed in previous molecular phylogenetic studies. To study the phylogeny of the immigrans group, we analyzed the nucleotide sequences of two nuclear genes, alcohol dehydrogenase (Adh) and glycerol-3-phosphate dehydrogenase (Gpdh), for 36 drosophilid species, including 12 species of the immigrans group. In the resultant phylogenetic trees, 10 species of the immigrans group (D. immigrans, D. formosana, D. ruberrima, D. albomicans, D. nasuta, D. neonasuta, D. pallidifrons, D. hypocausta, D. neohypocausta, D. siamana) consistently formed a clade (the immigrans group proper), although the phylogeny within this clade did not exactly correspond to the classification of species subgroups. However, D. annulipes and D. quadrilineata, both of which belong to the quadrilineata subgroup of the immigrans group, were not included in the immigrans group proper. Furthermore, we obtained the unexpected result that D. annulipes was included in a clade comprising Scaptomyza and Hawaiian Drosophila, together with D. maculinotata of the funebris group, although the phylogenetic relationships within this clade remain uncertain and need to be substantiated with further studies. Thus, according to the present study, the immigrans group is polyphyletic

Replication Data for: Should Candidates Smile to Win Elections? An Application of Automated Face Recognition Technology

Previous studies examining whether the faces of candidates affect election outcomes commonly measure study participants' subjective judgment of various characteristics of candidates, which participants infer based solely on the photographic images of candidates. We, instead, develop a smile index of such images objectively with automated face-recognition technology. The advantage of applying this new technology is that the automated process of measuring facial traits is by design independent of voters' subjective evaluations of candidate attributes, based on the images, and thus allows us to estimate “undiluted” effects of facial appearance per se on election outcomes. The results of regression analysis using Japanese and Australian data show that the smile index has statistically significant and substantial effects on the vote share of candidates even after controlling for other covariates