Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism

A Novel Neural Substrate for the Transformation of Olfactory Inputs into Motor Output

Anatomical and physiological experiments in the lamprey reveal the neural circuit involved in transforming olfactory inputs into motor outputs, which was previously unknown in a vertebrate

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi

Reactions of pulmonary emphysema patients before and after VRS - Forcusing on the rehabilitation, activity, surgery -

今まで内科的治療が主体であった肺気腫に対して,近年外科的治療(Volume Reduction Surgery 以後VRSと略す)が行われるようになった｡VRSを受ける患者の看護では,手術前後において, リハビリテーション(以後リハビリと略す)や機能回復に向けてのケアが必要不可欠とされる。そこで,本研究は肺気腫患者の適切な看護援助を検討するために,手術前後に示す肺気腫患者のリハビリや活動に対する反応を明らかにすることを目的とした｡対象者は当病棟に入院している肺気腫患者8名(VRS手術前8名,手術後はそのうちの6名である)で, リハビリ, 日常生活活動,呼吸,手術などについて,面接ならびに観察による調査を行った｡分析の結果,手術前においてリハビリでは≪義務感≫,頑張って行えば呼吸が楽になるという≪期待感≫,≪サポート≫,≪不安≫が,活動では≪活動の制限≫,手術では呼吸が楽になるのではという≪期待感≫,≪おまかせ≫,≪いちかばちかの賭け≫,≪不安≫,≪回復に向けての欲求の高まり≫が明らかになった｡手術後においてリハビリでは≪呼吸が楽になるための手段≫が, 日常生活活動では≪今の状態よりは良くなると いう期待感≫が,手術では≪達成感≫ と≪身体的苦痛≫が,将来については≪ささやかな欲求≫が明らかになった｡Pulmonary emphysema has been mainly treated with medicine, but recently VRS(volume reduction surgery) has been receiving much attention. In nursing care for VRS patients, it is important to help the patient improve his/her daily activities and recover physical function smoothly after surgery. The purpose of this study is to clarify the reactions of pulmonary emphysema patients before and after VRS for appropriate nursing. The subjects were eight pulmonary emphysema patients at a ward in Okayama University Hospital, but six of them completed both before and after VRS data collection. The data were collected by interview and observation, and from medical and nursing records. Contents of the interview included rehabilitation, daily activities, respiratory symptoms, operative stress, and so on. The results were as follows : , , , and on rehabilitation, on activity, , , , , and on surgery were extracted as pre-operative patients's reactions. on rehabilitation, on activity, and on surgery, on future were extracted as post-operative patients's reactions

In vivo and in vitro function of human UDP-galactose 4′-epimerase variants

Type III galactosemia results from reduced activity of the enzyme UDP-galactose 4′-epimerase. Five disease-associated alleles (G90E, V94M, D103G, N34S and L183P) and three artificial alleles (Y105C, N268D, and M284K) were tested for their ability to alleviate galactose-induced growth arrest in a Saccharomyces cerevisiae strain which lacks endogenous UDP-galactose 4′-epimerase. For all of these alleles, except M284K, the ability to alleviate galactose sensitivity was correlated with the UDP-galactose 4′-epimerase activity detected in cell extracts. The M284K allele, however, was able to substantially alleviate galactose sensitivity, but demonstrated near-zero activity in cell extracts. Recombinant expression of the corresponding protein in Escherichia coli resulted in a protein with reduced enzymatic activity and reduced stability towards denaturants in vitro. This lack of stability may result from the introduction of an unpaired positive charge into a bundle of three α-helices near the surface of the protein. The disparities between the in vivo and in vitro data for M284K-hGALE further suggest that there are additional, stabilising factors present in the cell. Taken together, these results reinforce the need for care in the interpretation of in vitro, enzymatic diagnostic tests for type III galactosemia