TY  - JOUR
AB  - Insulin signaling in the brain plays a critical role in metabolic control and cognitive function. Targeting insulinergic pathways in the central nervous system via peripheral insulin administration is feasible, but associated with systemic effects that necessitate tight supervision or countermeasures. The intranasal route of insulin administration, which largely bypasses the circulation and thereby greatly reduces these obstacles, has now been repeatedly tested in proof-of-concept studies in humans as well as animals. It is routinely used in experimental settings to investigate the impact on eating behavior, peripheral metabolism, memory function and brain activation of acute or long-term enhancements in central nervous system insulin signaling. Epidemiological and experimental evidence linking deteriorations in metabolic control such as diabetes with neurodegenerative diseases imply pathophysiological relevance of dysfunctional brain insulin signaling or brain insulin resistance, and suggest that targeting insulin in the brain holds some promise as a therapy or adjunct therapy. This short narrative review gives an overview over recent findings on brain insulin signaling as derived from human studies deploying intranasal insulin, and evaluates the potential of therapeutic interventions that target brain insulin resistance.
AU  - Santiago, J.C.
AU  - Hallschmid, M.
C1  - 55714
C2  - 46517
SP  - 180-190
TI  - Outcomes and clinical implications of intranasal insulin administration to the central nervous system.
JO  - Exp. Neurol.
VL  - 317
PY  - 2019
SN  - 0014-4886
ER  - 

TY  - JOUR
AB  - Parkinson's Disease (PD) is the most common neurodegenerative movement disorder. Autosomal-recessive mutations in the mitochondrial protein kinase PINK1 (PTEN-induced kinase 1) account for 1-2% of the hereditary early-onset cases. To study the mechanisms underlying disease development, we generated Pink1-deficient mice. In analogy to other genetic loss-of-function mouse models, Pink1(-/-) mice did not show morphological alterations in the dopaminergic system. As a consequence, no gross motor dysfunctions were observed indicating that these mice do not develop the cardinal symptoms of PD. Nonetheless, symptoms which develop mainly before bradykinesia, rigidity and resting tremor were clearly evident in Pink1-deficient mice. These symptoms were gait alterations and olfactory dysfunctions. Remarkably in the glomerular layer of the olfactory bulb the density of serotonergic fibers was significantly reduced. Concerning mitochondrial morphology, neurons in Pink1(-/-) mice had less fragmented mitochondria. In contrast, upon acute knock-down of Pink1 increased mitochondrial fragmentation was observed in neuronal cultures. This fragmentation was, however, evened out within days. Taken together, we demonstrate that Pink1-deficient mice exhibit behavioral symptoms of early phases of PD and present systematic experimental evidence for compensation of Pink1-deficiency at the cellular level. Thus, Pink1-deficient mice represent a model for the early phases of PD in which compensation may still impede the onset of neurodegeneration. Consequently, these mice are a valuable tool for studying Pink1-related PD development, as well as for searching for reliable PD biomarkers.
AU  - Glasl, L.
AU  - Kloos, K.
AU  - Giesert, F.
AU  - Roethig, A.
AU  - di Benedetto, B.*
AU  - Kühn, R.
AU  - Zhang, J.
AU  - Hafen, U.
AU  - Zerle, J.
AU  - Hofmann, A.
AU  - Hrabě de Angelis, M.
AU  - Winklhofer, K.F.*
AU  - Hölter, S.M.
AU  - Vogt Weisenhorn, D.M.
AU  - Wurst, W.
C1  - 7102
C2  - 29606
SP  - 214-227
TI  - Pink1-deficiency in mice impairs gait, olfaction and serotonergic innervation of the olfactory bulb.
JO  - Exp. Neurol.
VL  - 235
IS  - 1
PB  - Elsevier
PY  - 2012
SN  - 0014-4886
ER  - 

TY  - JOUR
AB  - The interaction of human mesenchymal stem cells (hMSCs) and tumor cells has been investigated in various contexts. HMSCs are considered as cellular treatment vectors based on their capacity to migrate towards a malignant lesion. However, concerns about unpredictable behavior of transplanted hMSCs are accumulating. In malignant gliomas, the recruitment mechanism is driven by glioma-secreted factors which lead to accumulation of both, tissue specific stem cells as well as bone marrow derived hMSCs within the tumor. The aim of the present work was to study specific cellular interactions between hMSCs and glioma cells in vitro. We show, that glioma cells as well as hMSCs differentially express connexins. and that they interact via gap-junctional coupling. Besides this so-called functional syncytium formation, we also provide evidence of cell fusion events (structural syncytium). These complex cellular interactions led to an enhanced migration and altered proliferation of both, tumor and mesenchymal stem cell types in vitro. The presented work shows that glioma cells display signs of functional as well as structural syncytium formation with hMSCs in vitro. The described cellular phenomena provide new insight into the complexity of interaction patterns between tumor cells and host cells. Based on these findings, further studies are warranted to define the impact of a functional or structural syncytium formation on malignant tumors and cell based therapies in vivo.
AU  - Schichor, C.*
AU  - Albrecht, V.*
AU  - Korte, B.*
AU  - Buchner, A.*
AU  - Riesenberg, R.*
AU  - Mysliwietz, J.
AU  - Paron, I.*
AU  - Motaln, H.*
AU  - Turnsek, T.L.*
AU  - Jurchott, K.*
AU  - Selbig, J.*
AU  - Tonn, J.C.*
C1  - 7993
C2  - 29995
SP  - 208-219
TI  - Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro.
JO  - Exp. Neurol.
VL  - 234
IS  - 1
PB  - Elsevier
PY  - 2012
SN  - 0014-4886
ER  - 

TY  - JOUR
AB  - Transplantation of dopaminergic ventral mesencephalic (VM) tissue into the basal ganglia of patients with Parkinson's disease (PD) shows at best moderate symptomatic relief in some of the treated cases. Experimental animal studies and clinical trials with allogenic and xenogenic pig-derived VM tissue grafts to PD patients indicate that one reason for the poor outcome of neural transplantation is the low survival and differentiation of grafted dopaminergic neurons. To improve dopaminergic cell survival through a genetherapeutic approach we have established and report here results of lipid-mediated transfer of the gene for human glial cell line-derived neurotrophic factor (GDNF) to embryonic (E27/28) porcine VM tissue kept as organotypic explant cultures. Treatment of the developing VM with two mitogens, basic fibroblast growth factor and epidermal growth factor, prior to transfection significantly increased transfection yields. Expression of human GDNF via an episomal vector could be detected by in situ hybridization and by the measuring of GDNF protein secreted into the culture medium. When compared to mock-transfected controls, VM tissue expressing recombinant GDNF contained significantly higher numbers of tyrosine hydroxylase-positive neurons in the cultured VM tissue. We conclude that lipid-mediated gene transfer employed on embryonic pig VM explant cultures is a safe and effective method to improve survival of dopamitnergic neurons and may become a valuable tool to improve allo- and xenotransplantation treatment in Parkinson's disease.
AU  - Bauer, M.
AU  - Meyer, M.*
AU  - Brevig, Th.*
AU  - Gasser, Th.*
AU  - Widmer, H.R.*
AU  - Zimmer, J.*
AU  - Ueffing, M.
C1  - 8948
C2  - 20449
SP  - 40-49
TI  - Lipid-Mediated Glial Cell Line-Derived Neurotrophic Factor Gene Transfer to Cultured Porcine Ventral Mesencephalic Tissue.
JO  - Exp. Neurol.
VL  - 177
IS  - 1
PB  -  Elsevier
PY  - 2002
SN  - 0014-4886
ER  -