Tobias Welt - Academia.edu (original) (raw)
Papers by Tobias Welt
Neuropsychopharmacology, Jan 4, 2006
In der vorliegenden Dissertation untersuchten wir mit Hilfe des psychopathologischen Tiermodells ... more In der vorliegenden Dissertation untersuchten wir mit Hilfe des psychopathologischen Tiermodells der HAB- und LAB-Ratten, welche sich nicht nur bezüglich ihrer genetisch determinierten Emotionalität und ihrer Stressbewältigungsstrategien, sondern auch hinsichtlich der Reaktivität der HPA-Achse unterscheiden, Effekte des Serotonin-Wiederaufnahmehemmers Paroxetin und von rTMS auf Verhalten und die neuroendokrine Regulation. Mit Hilfe des kombinierten DEX/CRH-Tests gelang es uns nachzuweisen, dass sich ein hohes Maß an angeborenem Angstverhalten in einer profunden Fehlregulation des Stresshormonsystems widerspiegelt. HAB-Tiere zeigten nach Verabreichung von Dexamethason einen verminderten Suppressionseffekt und die periphere Injektion von CRH führte zu einem deutlichen Anstieg der Plasmakonzentrationen von ACTH und Kortikosteron. Hierfür scheint intrahypothalamisch überexprimiertes und sezerniertes AVP verantwortlich zu sein, folglich führte auch die periphere Verabreichung eines V1-Re...
Absence of lymphocytes in both Rag2 ko mouse lines. 8 month-old Rag2 ko and PSAPP/Rag2 ko mice sh... more Absence of lymphocytes in both Rag2 ko mouse lines. 8 month-old Rag2 ko and PSAPP/Rag2 ko mice show virtually no B cells and CD4+ T cells, whereas age-matched WT and PSAPP transgenic animals show comparable numbers of B and CD4+ T cells as determined by FACS staining of CD45+ blood lymphocytes with antibodies against CD4 and the pan B-cell marker B220. In addition, no significant differences in the myeloid monocytic compartment (Ly6Chigh and Ly6Cintermediate) are observed among the four genotypes. # p = 0.05-0.1. *p
No difference in Thioflavin S-stained amyloid deposits between Rag2 ko and WT BM-transferred PSAP... more No difference in Thioflavin S-stained amyloid deposits between Rag2 ko and WT BM-transferred PSAPP mice. (A) Representative images of Thioflavin S-stained cortical amyloid deposits. (B) Quantitative analysis of Thioflavin S stainings 6 months after transplantation (at the age of 18 months) shows no difference in amyloid load and amyloid plaque number. Scale bar = 300 μm. n = 8–10 per group. (TIF 16319 kb)
No difference in APP processing. (A) Western blot analysis of cortical SDS extracts from 18-month... more No difference in APP processing. (A) Western blot analysis of cortical SDS extracts from 18-month-old PSAPP mice reconstituted with WT or Rag2 ko BM 6 months before sacrifice. Values were normalized to GAPDH. (B) Quantification reveals no significant differences in full length APP and APP C-terminal fragments (C99 and C83). n = 6 per group. (TIF 26355 kb)
Lack of amyloid plaque deposition at 3 months. (A) Thioflavin-S staining confirms absence of amyl... more Lack of amyloid plaque deposition at 3 months. (A) Thioflavin-S staining confirms absence of amyloid plaque deposition in 3 month-old PSAPP and age-matched PSAPP/Rag2 ko mice (representative images of cortical stainings are shown). (B) Quantitative MSD analysis of Aβ40 and Aβ42 in plasma and cortical tissue homogenized using sequential extraction to obtain different protein fractions: Tris soluble; SDS detergent soluble; formic acid soluble fraction (B). Statistical analysis reveals no differences in Aβ levels between PSAPP/Rag2 ko mice and the PSAPP mice at 3 months. Scale bar = 300 μm. n = 14–15 per group. (TIF 26755 kb)
Similar size of amyloid plaques analyzed by confocal microscopy. (A) Comparable average size of a... more Similar size of amyloid plaques analyzed by confocal microscopy. (A) Comparable average size of analyzed amyloid plaques between WT and Rag2 ko BM-reconstituted PSAPP mice at the age of 18 months. On average 12 Thioflavin S-stained amyloid plaques per mouse (n = 9 mice per group) were analyzed by laser scanning confocal microscopy. p = 0.711. (B) Trend towards an increased average number of Iba1-positive cells per plaque in the Rag2 ko BM-recipient PSAPP mice in comparison to the WT BM-reconstituted PSAPP mice at 18 months. Again, on average 12 Thioflavin S-stained amyloid plaques per mouse (n = 9 mice per group) were analyzed by laser scanning confocal microscopy. # p = 0.086. (TIF 8887 kb)
Science Translational Medicine, 2018
A human-derived antibody that is selective for misfolded SOD1 decreases motor impairments and boo... more A human-derived antibody that is selective for misfolded SOD1 decreases motor impairments and boosts survival in several rodent models of ALS.
Alzheimer's & Dementia, 2016
Molecular Psychiatry, 2016
Behavioural Brain Research, 2016
Journal of Cerebral Blood Flow & Metabolism, 2016
L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precurs... more L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precursor for the main central nervous system excitatory (L-glutamate) and inhibitory (γ-aminobutyric acid (GABA)) neurotransmitters. Concentrations of Gln and 13 other brain interstitial fluid amino acids were measured in awake, freely moving mice by hippocampal microdialysis using an extrapolation to zero flow rate method. Interstitial fluid levels for all amino acids including Gln were ∼5–10 times lower than in cerebrospinal fluid. Although the large increase in plasma Gln by intraperitoneal (IP) injection of 15N2-labeled Gln (hGln) did not increase total interstitial fluid Gln, low levels of hGln were detected in microdialysis samples. Competitive inhibition of system A (SLC38A1&2; SNAT1&2) or system L (SLC7A5&8; LAT1&2) transporters in brain by perfusion with α-(methylamino)-isobutyric acid (MeAIB) or 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) respectively, was tested. The data...
Acta Neuropathologica Communications, 2015
Journal of Alzheimer's disease : JAD, Jan 16, 2015
Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely es... more Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist...
The Journal of biological chemistry, Jan 26, 2014
Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of... more Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstra...
Translational Psychiatry, 2012
Neuropsychopharmacology, Jan 4, 2006
In der vorliegenden Dissertation untersuchten wir mit Hilfe des psychopathologischen Tiermodells ... more In der vorliegenden Dissertation untersuchten wir mit Hilfe des psychopathologischen Tiermodells der HAB- und LAB-Ratten, welche sich nicht nur bezüglich ihrer genetisch determinierten Emotionalität und ihrer Stressbewältigungsstrategien, sondern auch hinsichtlich der Reaktivität der HPA-Achse unterscheiden, Effekte des Serotonin-Wiederaufnahmehemmers Paroxetin und von rTMS auf Verhalten und die neuroendokrine Regulation. Mit Hilfe des kombinierten DEX/CRH-Tests gelang es uns nachzuweisen, dass sich ein hohes Maß an angeborenem Angstverhalten in einer profunden Fehlregulation des Stresshormonsystems widerspiegelt. HAB-Tiere zeigten nach Verabreichung von Dexamethason einen verminderten Suppressionseffekt und die periphere Injektion von CRH führte zu einem deutlichen Anstieg der Plasmakonzentrationen von ACTH und Kortikosteron. Hierfür scheint intrahypothalamisch überexprimiertes und sezerniertes AVP verantwortlich zu sein, folglich führte auch die periphere Verabreichung eines V1-Re...
Absence of lymphocytes in both Rag2 ko mouse lines. 8 month-old Rag2 ko and PSAPP/Rag2 ko mice sh... more Absence of lymphocytes in both Rag2 ko mouse lines. 8 month-old Rag2 ko and PSAPP/Rag2 ko mice show virtually no B cells and CD4+ T cells, whereas age-matched WT and PSAPP transgenic animals show comparable numbers of B and CD4+ T cells as determined by FACS staining of CD45+ blood lymphocytes with antibodies against CD4 and the pan B-cell marker B220. In addition, no significant differences in the myeloid monocytic compartment (Ly6Chigh and Ly6Cintermediate) are observed among the four genotypes. # p = 0.05-0.1. *p
No difference in Thioflavin S-stained amyloid deposits between Rag2 ko and WT BM-transferred PSAP... more No difference in Thioflavin S-stained amyloid deposits between Rag2 ko and WT BM-transferred PSAPP mice. (A) Representative images of Thioflavin S-stained cortical amyloid deposits. (B) Quantitative analysis of Thioflavin S stainings 6 months after transplantation (at the age of 18 months) shows no difference in amyloid load and amyloid plaque number. Scale bar = 300 μm. n = 8–10 per group. (TIF 16319 kb)
No difference in APP processing. (A) Western blot analysis of cortical SDS extracts from 18-month... more No difference in APP processing. (A) Western blot analysis of cortical SDS extracts from 18-month-old PSAPP mice reconstituted with WT or Rag2 ko BM 6 months before sacrifice. Values were normalized to GAPDH. (B) Quantification reveals no significant differences in full length APP and APP C-terminal fragments (C99 and C83). n = 6 per group. (TIF 26355 kb)
Lack of amyloid plaque deposition at 3 months. (A) Thioflavin-S staining confirms absence of amyl... more Lack of amyloid plaque deposition at 3 months. (A) Thioflavin-S staining confirms absence of amyloid plaque deposition in 3 month-old PSAPP and age-matched PSAPP/Rag2 ko mice (representative images of cortical stainings are shown). (B) Quantitative MSD analysis of Aβ40 and Aβ42 in plasma and cortical tissue homogenized using sequential extraction to obtain different protein fractions: Tris soluble; SDS detergent soluble; formic acid soluble fraction (B). Statistical analysis reveals no differences in Aβ levels between PSAPP/Rag2 ko mice and the PSAPP mice at 3 months. Scale bar = 300 μm. n = 14–15 per group. (TIF 26755 kb)
Similar size of amyloid plaques analyzed by confocal microscopy. (A) Comparable average size of a... more Similar size of amyloid plaques analyzed by confocal microscopy. (A) Comparable average size of analyzed amyloid plaques between WT and Rag2 ko BM-reconstituted PSAPP mice at the age of 18 months. On average 12 Thioflavin S-stained amyloid plaques per mouse (n = 9 mice per group) were analyzed by laser scanning confocal microscopy. p = 0.711. (B) Trend towards an increased average number of Iba1-positive cells per plaque in the Rag2 ko BM-recipient PSAPP mice in comparison to the WT BM-reconstituted PSAPP mice at 18 months. Again, on average 12 Thioflavin S-stained amyloid plaques per mouse (n = 9 mice per group) were analyzed by laser scanning confocal microscopy. # p = 0.086. (TIF 8887 kb)
Science Translational Medicine, 2018
A human-derived antibody that is selective for misfolded SOD1 decreases motor impairments and boo... more A human-derived antibody that is selective for misfolded SOD1 decreases motor impairments and boosts survival in several rodent models of ALS.
Alzheimer's & Dementia, 2016
Molecular Psychiatry, 2016
Behavioural Brain Research, 2016
Journal of Cerebral Blood Flow & Metabolism, 2016
L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precurs... more L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precursor for the main central nervous system excitatory (L-glutamate) and inhibitory (γ-aminobutyric acid (GABA)) neurotransmitters. Concentrations of Gln and 13 other brain interstitial fluid amino acids were measured in awake, freely moving mice by hippocampal microdialysis using an extrapolation to zero flow rate method. Interstitial fluid levels for all amino acids including Gln were ∼5–10 times lower than in cerebrospinal fluid. Although the large increase in plasma Gln by intraperitoneal (IP) injection of 15N2-labeled Gln (hGln) did not increase total interstitial fluid Gln, low levels of hGln were detected in microdialysis samples. Competitive inhibition of system A (SLC38A1&2; SNAT1&2) or system L (SLC7A5&8; LAT1&2) transporters in brain by perfusion with α-(methylamino)-isobutyric acid (MeAIB) or 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) respectively, was tested. The data...
Acta Neuropathologica Communications, 2015
Journal of Alzheimer's disease : JAD, Jan 16, 2015
Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely es... more Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist...
The Journal of biological chemistry, Jan 26, 2014
Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of... more Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstra...
Translational Psychiatry, 2012