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Prof. Dr. rer.nat. Anne Eckert

Faculty of Medicine
Profiles & Affiliations

Projects & Collaborations

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Cellular aging in-a-dish: Impact of stress

Research Project  | 1 Project Members

Aging is a risk factor for several of the world's most prevalent diseases, including neurodegenerative disorders. However, while much research has focused on age-related neurodegenerative disorders broadening our understanding of the underlying disease-specific molecular pathways, significantly fewer studies investigated the molecular biology of the aging brain in the absence of disease. Practical tools for studying brain aging encompass many model organisms. Since mouse models have some limitations regarding transferability to human physiology and lifespan, advanced human in vitro models are wanted. The fact that live human brain samples, such as neurons, are not as accessible slowed down progress in the field. The recent advent of technologies that enable adult human somatic cells to be reprogrammed into induced pluripotent stem cells (iPSCs) for the generation of neural cells as well as direct conversion into neural cells (induced neurons, iNs) has therefore provided a unique opportunity to investigate important aspects of CNS function in vitro . In contrast to iPSCs derived neurons, directly programmed iNs generated from aged donors' fibroblasts retain age-associated transcriptional signatures of the donor population and exhibit functional deficits in their capacity to properly compartmentalize nuclear and cytoplasmic proteins ( Mertens et al., 2016 , Mertens et al., 2015 ) suggesting that direct cell fate conversion bypassing pluripotency allows the identification of processes associated with aging and the modeling of human aging on a cellular level. However, many aging aspects were not yet investigated in this iNs model. Different hallmarks are generally considered to contribute to the aging process, e.g. mitochondrial failure, genomic instability, and telomere attrition. Together they determine the aging phenotype. The goal of the present proposal is therefore to further characterize and validate this advanced human neural in vitro model of aging by investigating six important age-related candidate features : i) in the first place we focus on mitochondrial dysfunction as a central player in the aging process, where many age-associated impairments converge on with a negative impact; ii) genome instability, iii) telomere attrition, iv) epigenetic alterations, v) loss of proteostasis, and vi) cellular senescence; in three different aging models : a) the classic cell model of normal human fibroblasts (NHFs) from healthy young and aged donors, b) the advanced cell model of human induced neurons (iNs) from the corresponding young and aged donor fibroblasts, c) neuronal aging in the mouse brain (the Thy1-mitoCFP mouse model expressing the cyan fluorescent protein only in neuronal mitochondria, especially in the hippocampus, allows the comprehensive analysis of age-related changes in mitochondrial morphology and dynamics). Thus the study will address the following questions: Do iNs retain important aging-related signatures besides the donor-age dependent transcriptomic signature demonstrated by Mertens et al. (2015)? Are stress approaches effective in mimicking cellular aging in iNs? Are the aging signatures of iNs relevant for the aging brain? Our study will increase our understanding of how well ''aged'' iNs are representative of human aging by modeling the aging process in vitro . The more complete the aging phenotype of the "aged" iNs model is, the better it can be establish as an unprecedented tool for new drug discoveries to maintain healthy brain aging that may also prevent various age-related brain disorders.

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Brain derived neurotrophic factor as a biomarker of insomnia

Research Project  | 4 Project Members

Brain-derived neurotrophic factor (BDNF) is a member of a family of growth factors located in the brain and peripheral tissues and plays an essential role in the neuronal cell differentiation, growth and survival. In the last decade, BDNF has become increasingly accepted as a central mediator of the effects of stress on neuronal plasticity. In a recent pilot study, our research group was the first to show that patients suffering from insomnia showed significantly decreased serum BDNF levels compared to sleep healthy controls. In the proposed project, we aim at assessing, whether BDNF may serve as a biomarker for insomnia on a larger scale across different diagnostic entities of sleep disorders and sleep healthy controls to verify the results of our exploratory investigation (Giese at al. 2013) and to elucidate the underlying mechanisms more closely. Moreover, given the relationship between sleep and cognitive performance, our research is also aimed in a second line, to extend our knowledge on the relationship between sleep and cognitive disturbances with reference to potential mediators. For that purpose, 62 male and female patients aged between 18 and 65 years suffering from insomnia according to DMS-IV criteria as well as a control group of 62 healthy, age and gender-matched controls will be enrolled in a prospective sleep center study performed at the Psychiatric University Clinics in Basel. Our main working hypothesis is that higher severity of insomnia is related to lower BDNF serum levels in patients suffering from insomnia (primary study outcome). As secondary objectives, the relationship between serum BDNF levels and objective sleep EEG parameters of sleep continuity (sleep onset latency, sleep duration, number of awakenings, wakefulness after sleep onset and sleep efficiency) and sleep EEG parameters of sleep architecture (stage 1 and 2, slow wave sleep and REM sleep), BDNF serum levels, BDNF signalling and cognition will be investigated in an explorative approach. Thus, we expect the following secondary outcomes: i.) Objective EEG sleep parameters indicating abnormalities of sleep continuity and sleep architecture are related to lower serum BDNF levels. ii.) Higher severity of insomnia is associated with decreased cognitive performance in attentional as well as memory-related cognitive performance. iii.) Lower BDNF serum levels are associated with lower cognitive performance in the cognitive test battery. iv.) Lower BDNF serum levels are associated with reduced pattern separation ability, thus indicating a hippocampal-dependent memory dysfunction. v.) Lower BDNF serum levels are associated with disturbed BDNF signalling pathways. If we can substantiate the role of BDNF as a marker of insomnia in a larger group of patients and across different diagnostic entities this has important implications for our understanding of the pathophysiology of insomnia. Once validated as a reliable marker of insomnia BDNF may serve as a research and diagnostic tool for a dimensional approach to insomnia that better reflects the underlying neurobiological mechanisms than mere categorical diagnostic attributions.

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Dissecting the neuroprotective role of neurosteroids in Alzheimer's disease: Modulation of bioenergetics and amyloid-ß/tau toxicity

Research Project  | 1 Project Members

Data from multilevel approaches indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimer's disease (AD). Among the steroids in decline is allopregnanolone (APα; a metabolite of progesterone) which was found to be reduced in the serum and brain of aged compared to young subjects. Moreover, AD patients showed an even further reduction in plasma and brain levels of APα relative to age-matched controls. In AD mice models, treatment with APα was able to reverse neurogenic AD deficits. More recent data revealed that APα was able to prevent cognitive deficits in transgenic mice when treatment started at pre-Aβ pathology state. Based on the promising results obtained with APα in transgenic AD mice, we started a collaboration with A.G. Mensah-Nygan (Strasbourg; France) to test four different analogues of APα (patent holder: A.G. Mensah-Nygan), which exhibited neuroprotective and/or neurogenic effects in spinal cord injury. Notably, our preliminary findings show that the analogues exhibited superior effects on ATP homeostasis when compared to the mother compound APα. Main working hypothesis Based on our previous and preliminary findings, we hypothesize that neurosteroids especially APα and its analogues have a beneficial impact on tau/Aβ-induced deficits in bioenergetics as well as dendritic processes and lead to a reduction of tau and Aβ pathology in AD models. For this approach, we will combine analyses in cell culture systems as well as transgenic mouse models. To identify the most promising APα analogue we will start in cellular systems that share key features with the in vivo models. While some evidence is provided for neuroprotective effects of neurosteroids, mainly APα, on Aß pathology, we are not aware of a single study well characterizing the effects of neurosteroids on tau pathology. Moreover, several studies investigated the modulation of bioenergetics by estrogen, our preliminary results, however, showed that this mode of action was not unique to estradiol, but was also relevant for APα. Thus, we would like to pursue four different objectives as part of this program: Aim A: We will firstly investigate the modulating effects of APα and its analogues in the presences of one pathological AD hallmark alone (overexpression of tau or APP). Thus, we will gain insights into the mechanisms interfering with tau-induced deficits in comparison with those of Aβ. Aim B: Secondly, by using an innovative TALEN approach we will investigate the effects of APα and its derivates on tau distribution, aggregation and cellular function. Aim C: Thirdly, we will determine whether APα and one of its analogues (selected after completion of in vitro screening) show similar beneficial effects on deficits in tau transgenic mice (pR5) in vivo and hamper the synergistic destruction caused by the combination of Aβ and tau in vivo (APP23xpR5) . Aim D: Fourthly, we will characterize the mode of action profile of APα in comparison with those of other neurosteroids (estradiol, testosterone, progesterone, DHEA) in vitro . The current approach opens up the opportunity to characterize promising therapeutic candidate/s for simultaneous promotion of bioenergetic function and neuritic processes to prevent or delay further progression of AD pathology.

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Advances in understanding the role of stress in health and mental disorders: Translational medicine approaches.

Research Project  | 3 Project Members

Stress, including severe psychological traumas, comprises one of the leading problems in today's society. Certainly, in South Africa, psychological trauma was rated one of the key challenges in an Essential National Health Research priority setting exercise. The adaptation to challenges from the environment and as well as to disturbances of the "milieu interne", is fundamentally linked to the activation of stress-responsive systems. The activation of these systems, i.e. the hypothalamus-pituitary-adrenal (HPA) system and the sympathoadrenergic system, is necessary for coping with stressors and for survival. However, the exaggerated or dysregulated activity of these systems not only renders human beings prone to psychiatric disease, but also to metabolic-endocrine disorders, heart disease and premature ageing. Against this background, the objectives of the seminar were: - To further the mutual transfer between basic neurosciences, preclinical stress research and clinical research. - To review the state-of-the-art knowledge on the pathophysiology of stress and stress-associated psychiatric disorders. - To elucidate specific stress-related mental health problems in the two different countries in order to focus on synergistic and complementary competencies in preclinical and clinical research (Switzerland versus South Africa). - To provide a platform for discussing issues, exchanging ideas and experience and promoting better understanding on the role of stress in health and mental disorders.- To establish networking among participants of the two countries.