TY  - JOUR
A1  - Massih, Bita
A1  - Veh, Alexander
A1  - Schenke, Maren
A1  - Mungwa, Simon
A1  - Seeger, Bettina
A1  - Selvaraj, Bhuvaneish T.
A1  - Chandran, Siddharthan
A1  - Reinhardt, Peter
A1  - Sterneckert, Jared
A1  - Hermann, Andreas
A1  - Sendtner, Michael
A1  - Lüningschrör, Patrick
T1  - A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS
JF  - Frontiers in Cell and Developmental Biology
N2  - The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND.
KW  - NMJ–neuromuscular junction
KW  - motoneuron (MN)
KW  - skeletal muscle
KW  - iPSC (induced pluripotent stem cells)
KW  - 3D cell culture
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304161
SN  - 2296-634X
VL  - 11
ER  - 
TY  - JOUR
A1  - Schischlevskij, Pavel
A1  - Cordts, Isabell
A1  - Günther, René
A1  - Stolte, Benjamin
A1  - Zeller, Daniel
A1  - Schröter, Carsten
A1  - Weyen, Ute
A1  - Regensburger, Martin
A1  - Wolf, Joachim
A1  - Schneider, Ilka
A1  - Hermann, Andreas
A1  - Metelmann, Moritz
A1  - Kohl, Zacharias
A1  - Linker, Ralf A.
A1  - Koch, Jan Christoph
A1  - Stendel, Claudia
A1  - Müschen, Lars H.
A1  - Osmanovic, Alma
A1  - Binz, Camilla
A1  - Klopstock, Thomas
A1  - Dorst, Johannes
A1  - Ludolph, Albert C.
A1  - Boentert, Matthias
A1  - Hagenacker, Tim
A1  - Deschauer, Marcus
A1  - Lingor, Paul
A1  - Petri, Susanne
A1  - Schreiber-Katz, Olivia
T1  - Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives
JF  - Brain Sciences
N2  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
KW  - amyotrophic lateral sclerosis (ALS)
KW  - informal caregiving
KW  - caregiver burden
KW  - functional status
KW  - decreasing autonomy
KW  - depression
KW  - anxiety
KW  - health-related quality of life
KW  - socioeconomic status
KW  - psychological support
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240981
SN  - 2076-3425
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Peseschkian, Tara
A1  - Cordts, Isabell
A1  - Günther, René
A1  - Stolte, Benjamin
A1  - Zeller, Daniel
A1  - Schröter, Carsten
A1  - Weyen, Ute
A1  - Regensburger, Martin
A1  - Wolf, Joachim
A1  - Schneider, Ilka
A1  - Hermann, Andreas
A1  - Metelmann, Moritz
A1  - Kohl, Zacharias
A1  - Linker, Ralf A.
A1  - Koch, Jan Christoph
A1  - Büchner, Boriana
A1  - Weiland, Ulrike
A1  - Schönfelder, Erik
A1  - Heinrich, Felix
A1  - Osmanovic, Alma
A1  - Klopstock, Thomas
A1  - Dorst, Johannes
A1  - Ludolph, Albert C.
A1  - Boentert, Matthias
A1  - Hagenacker, Tim
A1  - Deschauer, Marcus
A1  - Lingor, Paul
A1  - Petri, Susanne
A1  - Schreiber-Katz, Olivia
T1  - A nation-wide, multi-center study on the quality of life of ALS patients in Germany
JF  - Brain Sciences
N2  - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
KW  - Amyotrophic Lateral Sclerosis (ALS)
KW  - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5)
KW  - ALS treatment
KW  - “bulbar-onset” ALS (bALS)
KW  - “limb-onset” ALS (lALS)
KW  - EuroQol Five Dimension Five Level Scale (EQ-5D-5L)
KW  - health-related quality of life (HRQoL)
KW  - quality of life (QoL)
KW  - symptom-specific treatment
KW  - assistive devices
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147
SN  - 2076-3425
VL  - 11
IS  - 3
ER  - 
TY  - JOUR
A1  - Fauser, Mareike
A1  - Weselek, Grit
A1  - Hauptmann, Christine
A1  - Markert, Franz
A1  - Gerlach, Manfred
A1  - Hermann, Andreas
A1  - Storch, Alexander
T1  - Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain
JF  - Frontiers in Neuroanatomy
N2  - The major catecholamines—dopamine (DA) and norepinephrine (NE)—are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM\(^{2+}\) cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM\(^{2+}\) cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM\(^{2+}\) cell counts) with their NE levels (r = −0.932; p < 0.001), but not their DA levels (r = 0.440; p = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development.
KW  - brain development
KW  - ventricular zone
KW  - catecholamines
KW  - norepinephrine
KW  - dopamine
KW  - neurogenesis
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212485
VL  - 14
ER  - 
TY  - JOUR
A1  - Weselek, Grit
A1  - Keiner, Silke
A1  - Fauser, Mareike
A1  - Wagenführ, Lisa
A1  - Müller, Julia
A1  - Kaltschmidt, Barbara
A1  - Brandt, Moritz D.
A1  - Gerlach, Manfred
A1  - Redecker, Christoph
A1  - Hermann, Andreas
A1  - Storch, Alexander
T1  - Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche
JF  - Stem Cells
N2  - The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
KW  - adult neurogenesis
KW  - hippocampus
KW  - noradrenaline
KW  - norepinephrine
KW  - olfactory bulb neurogenesis
KW  - subventricular zone
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218250
VL  - 38
IS  - 9
SP  - 1188
EP  - 1201
ER  - 
TY  - JOUR
A1  - Dupuis, Luc
A1  - Dengler, Reinhard
A1  - Heneka, Michael T.
A1  - Meyer, Thomas
A1  - Zierz, Stephan
A1  - Kassubek, Jan
A1  - Fischer, Wilhelm
A1  - Steiner, Franziska
A1  - Lindauer, Eva
A1  - Otto, Markus
A1  - Dreyhaupt, Jens
A1  - Grehl, Torsten
A1  - Hermann, Andreas
A1  - Winkler, Andrea S.
A1  - Bogdahn, Ulrich
A1  - Benecke, Reiner
A1  - Schrank, Bertold
A1  - Wessig, Carsten
A1  - Grosskreutz, Julian
A1  - Ludolph, Albert C.
T1  - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis
JF  - PLoS One
N2  - Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). 
Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. 
Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.
KW  - ALS
KW  - transgenic mouse model
KW  - central nervous system
KW  - nonalcoholic steatohepatitis
KW  - PPAR-gamme
KW  - hexanucleotide repeat
KW  - disease progression
KW  - delays progression
KW  - SOD1 mutations
KW  - monocycline
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255
VL  - 7
IS  - 6
ER  -