Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

The pathology of Alzheimer's disease (AD) is characterized by amyloid plaques (aggregates of amyloid-β (Aβ)) and neurofibrillary tangles (aggregates of tau) and is accompanied by mitochondrial dysfunction, but the mechanisms underlying this dysfunction are poorly understood. In this review, we discuss the critical role of mitochondria and the close inter-relationship of this organelle with the two main pathological features in the pathogenic process underlying AD. Moreover, we summarize evidence from AD post-mortem brain as well as cellular and animal AD models showing that Aβ and tau protein trigger mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. A vicious cycle as well as several vicious circles within the cycle, each accelerating the other, can be drawn, emphasizing the synergistic deterioration of mitochondria by tau and Aβ

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer's disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8months, resulting in a depolarized mitochondrial membrane potential. At 12months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in viv

Manuelle Medizin aus Sicht der Anwender: eine qualitative Studie mit Ärzten

Hintergrund: Manuelle Medizin (MM) hat einen hohen Stellenwert in der ambulanten Versorgung von Beschwerden des Bewegungsapparats. Trotz Vorliegen zahlreicher randomisiert-kontrollierter Studien und Meta-Analysen im Bereich der MM ist die Bewertung aufgrund verschiedener Schulen und Techniken teilweise schwierig. Ziel der vorliegenden Studie war es, bei der großen Beliebtheit dieser Therapieform die Motivation und Erfahrungen von Ärzten bezüglich der Anwendung von MM in der täglichen Praxis zu ergründen. Methoden: Im Rahmen eines qualitativen Forschungsansatzes wurden 21 semi-strukturierte, telefonische Einzelinterviews mit Ärzten mit der Zusatzqualifikation für MM durchgeführt. Die Rekrutierung erfolgte über die Deutsche Gesellschaft für Manuelle Medizin sowie über einen Verteiler von Ärzten, die an Forschungsfragen zu MM interessiert sind. Die Interviews wurden aufgezeichnet, transkribiert und, unterstützt durch das Computerprogramm Atlas.ti, inhaltsanalytisch ausgewertet. Ergebnisse: Als Hauptmotivation für die Anwendung von MM wurde eine Stärkung der Arzt-Patienten-Beziehung durch einen unmittelbaren Zugang zum Patienten mit schnellen Behandlungserfolgen geschildert. Weitere beschriebene Aspekte sind die Einfachheit der Methode, die Unabhängigkeit von räumlichen oder apparativen Gegebenheiten und die damit verbundenen niedrigen Kosten. Positive, als direkt die Zufriedenheit mit MM beeinflussend beschriebene Faktoren sind die Möglichkeit, eigene Fähigkeiten zu nutzen, den Patienten zu einem gesunden Lebensstil zu motivieren und die Dankbarkeit des Patienten. Als Aspekte, welche die Zufriedenheit negativ beeinflussen, wurden die schlechte Vergütung der Therapie, die unklare Evidenzlage, die Anwendung bei oft selbstlimitierenden Krankheiten und das Risiko schwerwiegender Nebenwirkungen sowie die Gefahr einer iatrogenen Fixierung genannt. Schlussfolgerungen: Die Ergebnisse dieser Studie zeigen eine große Bandbreite von zumeist positiven Sichtweisen und Erfahrungen von Ärzten bei der Anwendung von MM. Dem Wunsch nach dem unmittelbar heilenden Handeln scheint durch MM begegnet zu werden. Die MM scheint als willkommene Abwechslung zur alltäglichen Berufsausübung zu dienen, die als distanziert wahrgenommen wird

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer’s disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8 months, resulting in a depolarized mitochondrial membrane potential. At 12 months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in vivo

Teaching this class drives me nuts! - Examining the Person and Context Specificity of Teacher Emotions

Teachers' emotions are critically important for the quality of classroom instruction, and they are key components of teachers' psychological well-being. Past research has focused on individual differences between teachers, whereas within-teacher variation across contexts has rarely been considered. As such, the present research addresses the long-standing yet unresolved person-situation debate pertaining to the emotional experiences of teachers. In two diary studies (N = 135, 70% female, and N = 85, 28% female),we examined the role of person, academic subject, and group of students for teacher emotions;focusing on three of the most salient emotions found in teachers: enjoyment, anger, and anxiety. Findings from multi-level analysis confirmed the person specificity of enjoyment, anger, and, in particular, anxiety. In addition, underscoring the existence of within-teacher variability, findings supported that teachers' emotions considerably varied depending on the subject and group of students taught, particularly so for enjoyment and anger. Implications of the person and context specificity of teacher emotions are discussed in relation to assessments and intervention programs aiming to improve teachers' emotional lives in the classroom

Alzheimer's Disease, Oestrogen and Mitochondria: an Ambiguous Relationship

Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ- and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ-ABAD interactio

Mesenchymal Stem Cells Promote Oligodendroglial Differentiation in Hippocampal Slice Cultures

We have previously shown that soluble factors derived from mesenchymal stem cells (MSCs) induce oligodendrogenic fate and differentiation in adult rat neural progenitors (NPCs) in vitro. Here, we investigated if this pro-oligodendrogenic effect is maintained after cells have been transplanted onto rat hippocampal slice cultures, a CNS-organotypic environment. We first tested whether NPCs, that were pre-differentiated in vitro by MSC-derived conditioned medium, would generate oligodendrocytes after transplantation. This approach resulted in the loss of grafted NPCs, suggesting that oligodendroglial pre-differentiated cells could not integrate in the tissue and therefore did not survive grafting. However, when NPCs together with MSCs were transplanted in situ into hippocampal slice cultures, the grafted NPCs survived and the majority of them differentiated into oligodendrocytes. In contrast to the prevalent oligodendroglial differentiation in case of the NPC/MSC co-transplantation, naive NPCs transplanted in the absence of MSCs differentiated predominantly into astrocytes. In summary, the pro-oligodendrogenic activity of MSCs was maintained only after co-transplantation into hippocampal slice cultures. Therefore, in the otherwise astrogenic milieu, MSCs established an oligodendrogenic niche for transplanted NPCs, and thus, co-transplantation of MSCs with NPCs might provide an attractive approach to re-myelinate the various regions of the diseased CNS. Copyright (C) 2009 S. Karger AG, Base

Electrophysiological Assessment of the Deltoid Muscle after Minimally Invasive Treatment of Proximal Humerus Fractures - A Clinical Observation

The minimal anterolateral acromial approach offers a less invasive access to the proximal humerus. Functional impairment following this procedure may be caused by paresis of the deltoid muscle as a result of iatrogenic injury to the axillary nerve. It was addressed whether electromyography (EMG) of the deltoid muscle gives evidence for an axillary nerve lesion in association with the minimal anterolateral acromial approach

ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein

Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism

Insights into mitochondrial dysfunction: aging, amyloid-β, and tau-A deleterious trio

Significance: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-β [Aβ]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical Issues: In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Aβ and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging, Aβ, and tau protein" triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aβ and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon