Les mitochondries sont en charge de la bioénergétique cellulaire, tout particulièrement dans le cerveau humain, au sein duquel les neurones sont extrêmement demandeurs en énergie et hautement dépendant de la phosphorylation oxydative. En effet, celles-ci génèrent un potentiel énergétique grâce à une chaîne de transport d’électrons, ou chaîne respiratoire, composée de quatre complexes protéiques ancrés dans la membrane interne mitochondriale. La chaine respiratoire permet la production d’énergie via la phosphorylation oxydative d’ADP en ATP par l’ATP synthéase dans la matrice mitochondriale. Le premier complexe (CI) de la chaîne est composé de 45 sous-unités protéiques (dont 44 différentes). En tant que premier enzyme de la phosphorylation oxydative, il joue un rôle d’initiateur et est essentiel pour la production d'énergie cellulaire. Un défaut d’assemblage du CI se traduit par d’importantes conséquences sur la bioénergétique cellulaire et augmente la production d’espèces réactives de l’oxygène (ROS), pouvant être à l'origine de divers troubles mitochondriaux, parmi lesquels certains processus neurodégénératifs. La bonne intégration des sous-unités et cofacteurs composant le CI est par conséquent primordiales et requièrent la participation de facteurs d’assemblage jouant le rôle de chaperonnes afin de stabiliser les sous-unités et faciliter leur intégration au sein de l'enzyme complète. De plus, certaines fonctions additionnelles à leur rôle d’assemblage peuvent intervenir dans d’autres processus cellulaire régulant l’activité métabolique.Le fonctionnement des facteurs d'assemblage du CI au niveau moléculaire demeure encore obscur. Néanmoins, il est admis que la plupart des facteurs d'assemblages identifiés sont actifs dès le début de l'assemblage, particulièrement pour l'incorporation des sous-unités membranaires. Récemment un groupe de facteurs d’assemblage composés des protéines NDUFAF1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1), ACAD9 (Acyl-CoA dehydrogenase 9), ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway), et potentiellement TMEM126B (Transmembrane protein 126B) and TIMMDC1 (Translocase of inner mitochondrial membrane domain-containing 1) est désigné sous l'appellation complexe d’assemblage du complexe mitochondrial I (MCIA). Cependant, la composition et la stœchiométrie de ce dernier restent inconnus, excluant ainsi toute compréhension satisfaisante de sa structure et de son importance dans les mécanismes à l'oeuvre dans l’assemblage du CI.Cette thèse a pour but les caractérisations des facteurs d’assemblage ACAD9, ECSIT and NDUFAF1 grâce à un ensemble d’approches biochimiques et biophysiques dans le but de déterminer les mécanismes moléculaires et la cartographie des interactions impliqués dans l’assemblage du complexe MCIA. / Mitochondria are responsible for bioenergetics, particularly critical in the human brain, where neurons are extremely energy demanding and highly dependent on the oxidative phosphorylation (OXPHOS) system. They generate energetic potential through the electron transport chain (ETC), also named the respiratory chain, which is composed of four protein complexes embedded into the mitochondrial inner membrane (MIM) to enable the phosphorylation of ADP into ATP by the ATP synthase in the mitochondrial matrix. Together these complexes form the OXPHOS system. Complex I (CI), the first enzyme of the respiratory chain, is composed of 45 protein subunits (of which 44 are different) and initiates the OXPHOS system, being essential in cellular energy production. Defects in CI assembly severally impair ATP production, increase the production of reactive oxygen species (ROS) and are implicated in several mitochondrial disorders, including neurodegenerative diseases. The integration of the 45 subunits and the insertion of cofactors into the nascent complex requires the help of assembly factors. Assembly factors may act as chaperones that stabilize the intermediate complexes or subunits and help to attach them to other intermediate assemblies to build the complete enzyme. However, they may also have additional functions besides their requirement for CI assembly, in line with the emerging evidence that mitochondria are involved with various (sub)cellular processes that regulate cell metabolic activity.How CI assembly factors function at the molecular level is currently unclear, with very little structural information available. Nevertheless, it is thought that most identified assembly factors are involved in early assembly, more specifically in the incorporation of hydrophobic membrane subunits. Recently, the CI assembly factors NDUFAF1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1), ACAD9 (Acyl-CoA dehydrogenase 9), ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway), and potentially TMEM126B (Transmembrane protein 126B) and TIMMDC1 (Translocase of inner mitochondrial membrane domain-containing 1) were proposed to form the so-called mitochondrial complex I assembly (MCIA) complex. However, the composition and stoichiometry of the MCIA complex are unknown, which precludes a proper understanding of the structural and mechanistic bases for building-up assembly intermediates and how the MCIA complex achieves specificity.This thesis pursues the characterisation of the MCIA core components ACAD9, ECSIT and NDUFAF1, mapping their interactions and characterising their structures using a combination of biophysical and biochemical approaches in order to elucidate the molecular mechanisms underlying the MCIA complex formation.

Alzheimer’s disease is a debilitating illness that is the 6th leading cause of death among the elderly. The treatment of Alzheimer’s requires multiple interventions due to the complexity of the disease. The interdisciplinary group (IDG) model of care is considered a best practice for patients’ medical management (Molyneux, 2001). The IDG focuses on a holistic approach, which includes both patients and their caregivers. The IDG in hospice consists of professionals from different clinical disciplines whose collaborative knowledge and skills assist in caring for patients and their families. This study focused on what works well in an exemplary IDG, using appreciative inquiry as to the method of inquiry. Data were collected from 6 participants of an exemplary IDG caring for patients diagnosed with Alzheimer’s disease. The data were analyzed using the appreciative inquiry 4-D cycle: Discovery, Dream, Design, and Destiny. In the Discovery phase, 10 themes emerged, showing the connection to the Dream phase. The Dream phase led into the Design phase, focusing on provocative propositions, which bridge the best of what is with what might be. This then connected with the Destiny phase, bringing the dreams of the future to the present. I found that what works well with this exemplary IDG is the connection to other members of the team and the larger system; dedication; commitment; and valuing of team members, their patients, and patients’ families. The findings suggested the need for increased training of marriage and family therapists for IDG settings as the systemic thinking of marriage and family therapy appears to be a good fit for the IDG.

A higher prevalence and incidence of dementia is found in Hispanic/Latino older adults. Therefore, valid instruments are necessary to assess cognitive functioning in this population group. Our aim was to review existing articles that have examined and reported on the validity of cognitive assessment tools in Hispanic/Latino population groups in the United States.

Bakgrund: Årligen insjuknar cirka 20 000 personer i Alzheimers sjukdom i Sverige. Olika förändringar av strukturen i hjärnan sker, vilket leder till blockering av nervimpulser som ger negativ påverkan på hjärnans minnescentrum. Alzheimers sjukdom beskrivs som anhörigas sjukdom då den har inverkan på deras livsvärld. Därmed ökar behovet av stöd från hälso- och sjukvården samt de kommunala verksamheterna. Syfte: Syfte var att belysa upplevelser av att vara anhörig till en familjemedlem med Alzheimers sjukdom. Metod: Examensarbetet baserades på kvalitativ metod med analys av berättelser (narrativ) utifrån självbiografier. Analysen utgick ifrån fyra självbiografier. Resultat: Resultatet presenterades med två teman: Kunna anpassa till den förändrade livssituationen och Upplevelser av sorg och glädje. Anhöriga upplevde bristande kunskaper och information om Alzheimers sjukdom samt förändring i vardagen, relationer och syn på döden. Konklusion: Anhöriga upplevde förändring av livsvärden när en familjemedlem insjuknar i Alzheimers sjukdom. Sjuksköterskors erfarenheter och bemötande har betydande roll för anhörigas syn på vården. / Background: Approximately 20 000 people become ill annually with Alzheimer's disease in Sweden. Several changes occur in the structure of the brain, which leads to blockage of nerve impulses that gives negative effects on the brain’s memory center. It is described as the disease of relatives since it has a direct impact on their lifeworld. Therefore, the need for support of healthcare and municipal activities increases. Aim: The aim was to illustrate the experiences of being a relative to a family member who has become ill with Alzheimer’s disease. Method: The method of the thesis was qualitative method with a narrative analysis based on autobiographies. Four autobiographies were included in the analysis.  Findings: The finding is presented in two themes: Adapting to the changed life situation and Experiences of sorrow and joy. Relatives experienced a lack of knowledge and information about Alzheimer’s disease and change in everyday life, relationships and view of death. Conclusion: The relatives’ experienced a change in their lifeworld when a family member becomes ill with Alzheimer’s disease. Nurses’ experiences and encounters has an important role regarding how relatives view the healthcare.

Investigating similarities among neurological diseases can provide insight into disease processes. Two prominent commonalities of neurological diseases are the formation of amyloid deposits and altered ammonia and glutamate metabolism. Computational techniques were used to explore these processes in several neurological diseases. Residue interaction networks (RINs) abstract protein structure into a series of nodes (representing residues) and edges (representing connections between residues likely to interact). Analyzing the RINs of monomeric forms of amyloidogenic proteins for common network features revealed similarities not previously known. First, amyloidogenic variants of lysozyme were used to demonstrate the usefulness of RINs to the study of amyloidogenic proteins. Next, I compared RINs of amyloidogenic proteins with randomized control networks and a group of real protein controls and found similarities in network structures unique to amyloidogenic proteins. The use of 3D structure data and network structure data of amyloid-beta (1-42) (Abeta42) in a hydrophobic, membrane-mimicking solvent led to the identification of an interaction between Val24 and Ile31 as potentially involved in preventing Abeta aggregation. Since Abeta causes oxidative damage, since the ammonia metabolism enzyme glutamine synthetase is particularly susceptible to oxidative damage, and since glutamate plays a central role in neuronal function, I expanded my research to include the study of ammonia and glutamate metabolism in neurological diseases. A computational model of the effects of the interactions between the amount of dietary protein and the activities of ammonia metabolism enzymes on blood and brain ammonia levels supports potentially important roles for these enzymes in the protection of neural function. Next, I reviewed the role of amino acid catabolism in Alzheimer’s disease (AD). Common tissue pathology and the ability of memantine, an NMDA receptor antagonist, to relieve symptoms in patients and animal models of AD, major depressive disorder (MDD), and type 2 diabetes (T2D) further support a role for ammonia and glutamate metabolism in disease. Lastly, I found that single nucleotide polymorphisms (SNPs) in select ammonia metabolism genes are associated with these three diseases. The results presented in this dissertation demonstrate that investigating neurological diseases using computational approaches can provide great insight into the common underlying pathologies.

Linear mixed model (LMM) has the advantage of modeling the corelated data. Alzheimer’s disease (AD) is a chronic neurogenerative disease that affects the brain of the subject. No study was found to study the longitudinal effect of apolipoprotein E epsilon 4 (APOE4) genotype on the logical memory test total score in AD. A longitudinal data of 844 with AD, 2167 with cognitive normal (CN), and 4472 with mild cognitive impairment (MCI) participants who underwent logical memory examination test in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were investigated. Episodic memory of the study participants was monitored based on a short story told to the participants and then participants asked to recall what was told. The multivariate LMM was used to determine the longitudinal changes in the logical memory test total score adjusting for age and sex. The Akaike information criterion (AIC) statistic and the Bayesian information criterion (BIC) statistic were used to select the best covariance structure. The repeated measures longitudinal analysis was performed using PROC MIXED in SAS 9.4. Both AIC and BIC statistics favor the unstructured correlated structure (UN). Using a UN model in the LMM, the APOE gene was is significantly associated with logical memory test total score (pUN covariance structure is the best. This study provided the first evidence of the effect of APOE4 genotype on the logical memory related to AD.

I Sverige är demens den fjärde största sjukdomen och i världen förväntas nästan en fördubbling av incidensen ske till år 2030. Det är därför viktigt att finna alter-nativa, kostnadseffektiva behandlingsformer som är effektiva på denna specifika grupp. Syftet med studien var att undersöka djurs hälsofrämjande effekter i vården av individer med diagnosen Alzheimers eller annan demenssjukdom. En litteratur-studie gjordes där tio artiklar redovisas i resultatet. Djur inom Alzheimers- och demensvården visar på positiva effekter i form av minskad agitation och oro, ökad verbal förmåga, ökad kroppskontakt och kontaktsökande samt förbättrad nutrition hos dessa individer. Slutsatsen är att djur kan vara ett effektivt komplement i om-vårdnaden av individer med Alzheimers eller annan demenssjukdom. / In Sweden dementia is the fourth most common disease and in the world the numbers are expected to be twice as high in the year of 2030. Therefore it is im-portant to find alternative, cost-effective forms of treatments that are effective on this specific group. The aim of the study was to examine the health effects of ani-mals in the care of individuals diagnosed with Alzheimer’s disease or other re-lated diseases. A literature review including ten articles in the result was made. Animals in Alzheimer’s and dementia care indicate positive effects such as de-creased agitation and anxiety, increased verbalizations, increase in tactile contact and seeking for contact and improved nutrition among these individuals. The con-clusion is that animals can serve as an effective complement in the care of indi-viduals with Alzheimer’s disease or other related diseases.

OBJECTIVE: Piwi-interacting RNAs (piRNAs) represent a molecular feature shared by all nonaging biological systems, including the germline and somatic cancer stem cells, which display an indefinite renewal capacity and lifespan-stable genomic integrity and are potentially immortal. Here, we tested the hypothesis that piRNA is a critical genetic determinant of aging in humans. METHODS: Expression of transcriptome-wide piRNAs (n=24k) was profiled in the human prefrontal cortex of 12 subjects (84.9±9.5, range 68-100, years of age) using microarray technology. We examined the correlation between these piRNAs' expression levels and age, adjusting for covariates including disease status. RESULTS: A total of 9,453 piRNAs were detected in brain. Including seven intergenic and three intronic piRNAs, ten piRNAs were significantly associated with age after correction for multiple testing (|r|=0.9; 1.9×10≤p≤9.9×10). CONCLUSION: We conclude that piRNAs might play a potential role in determining the years of survival of humans. The underlying mechanisms might involve the suppression of transposable elements (TEs) and expression regulation of aging-associated genes.

京都大学 / 新制・論文博士 / 博士(医科学) / 乙第13503号 / 論医科博第9号 / 新制||医科||10(附属図書館) / (主査)教授 林 康紀, 教授 髙橋 良輔, 教授 井上 治久 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.