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Reinhard Schliebs - One of the best experts on this subject based on the ideXlab platform.
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hypoxic stress brain vascular system and β amyloid a primary cell culture study
Nutritional Neuroscience, 2015Co-Authors: Abebe Muche, Susanne Bürger, Thomas Arendt, Reinhard SchliebsAbstract:AbstractThis study stresses the hypothesis whether hypoxic events contribute to formation and deposition of β-amyloid (Aβ) in cerebral blood vessels by affecting the processing of endothelial amyloid precursor protein (APP). Therefore, cerebral endothelial cells (ECs) derived from transgenic Tg2576 Mouse brain, were subjected to short periods of hypoxic stress, followed by assessment of formation and secretion of APP cleavage products sAPPα, sAPPβ, and Aβ as well as the expression of endothelial APP. Hypoxic stress of EC leads to enhanced secretion of sAPPβ into the culture medium as compared to normoxic controls, which is accompanied by increased APP expression, induction of vascular endothelial growth factor (VEGF) synthesis, nitric oxide production, and differential changes in endothelial p42/44 (ERK1/2) expression. The hypoxia-mediated up-regulation of p42/44 at a particular time of incubation was accompanied by a corresponding down-regulation of the phosphorylated form of p42/44. To reveal any role o...
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Monitoring blood flow alterations in the Tg2576 Mouse model of Alzheimer's disease by in vivo magnetic resonance angiography at 17.6 T
NeuroImage, 2011Co-Authors: Firat Kara, Reinhard Schliebs, E.s. Van Dongen, M.a. Van Buchem, H. J. M. De Groot, A. AliaAbstract:Many neurodegenerative diseases including Alzheimer's disease are linked to abnormalities in the vascular system. In AD, the deposition of amyloid β (Aβ) peptide in the cerebral vessel walls, known as cerebral amyloid angiopathy (CAA) is frequently observed, leading to blood flow abnormalities. Visualization of the changes in vascular structure is important for early diagnosis and treatment. Blood vessels can be imaged non-invasively by magnetic resonance angiography (MRA). In this study we optimized high resolution MRA at 17.6 T to longitudinally monitor morphological changes in cerebral arteries in a Tg2576 Mouse model, a widely used model of AD. Our results at 17.6 T show that MRA significantly benefits from the ultra-high magnetic field strength especially to visualize smaller vessels. Visual and quantitative analysis of MRA results revealed severe blood flow defects in large and medium sized arteries in Tg2576 mice. In particular blood flow defects were observed in the middle cerebral artery (MCA) and in the anterior communicating artery (AComA) in Tg2576 mice. Histological data show that Aβ levels in the vessel wall may be responsible for impaired cerebral blood flow, thereby contributing to the early progression of AD. To our knowledge this is the first ultra-high field MRA study monitoring blood flow alterations longitudinally in living Tg2576 mice, consequently providing a powerful tool to test new therapeutic intervention related to CAA in a Mouse model of AD.
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Cell proliferation and total granule cell number in dentate gyrus of transgenic Tg2576 Mouse.
Acta neurobiologiae experimentalis, 2010Co-Authors: Amadi O. Ihunwo, Reinhard SchliebsAbstract:This report provides in vivo evidence of adult neurogenesis and the total granule cell count in the dentate gyrus of the Tg2576 Mouse model of Alzheimer's disease. Mice were deeply anaesthetized and perfused with 4 percent buffered paraformaldehyde. Brains were removed and post-fixed in the same fixative overnight. Following equilibration in 30 percent sucrose, 30 micrometer sections were cut in sagittal plane in freezing microtome for immunohistochemistry and 20 micrometer from plastic embedded brains. Thioflavin-S confirmed the presence of amyloid plaques in the Tg2576 mice. Cell proliferation in the subventricular zone and dentate gyrus of hippocampus were observed with Ki-67 and doublecortin markers. Using optical fractionator, total granule number was estimated to be 445,280 per hemisphere in the 18-month-old Tg2576 Mouse. Cell proliferation tends to end in the dentate gyrus but continues in the SVZ and the total granule cell number was less compared to normal laboratory and wild rodents.
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Vascular endothelial growth factor (VEGF) affects processing of amyloid precursor protein and β-amyloidogenesis in brain slice cultures derived from transgenic Tg2576 Mouse brain
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009Co-Authors: Susanne Bürger, Monika Noack, Ludmil Kirazov, Evgeni P. Kirazov, Cyrill L. Naydenov, Elena Kouznetsova, Yousef Yafai, Reinhard SchliebsAbstract:The up-regulation of the angiogenic vascular endothelial growth factor (VEGF) in brains of Alzheimer patients in close relationship to beta-amyloid (Abeta) plaques, suggests a link of VEGF action and processing of the amyloid precursor protein (APP). To reveal whether VEGF may affect APP processing, brain slices derived from 17-month-old transgenic Tg2576 mice were exposed with 1ng/ml VEGF for 6, 24, and 72h, followed by assessing cytosolic and membrane-bound APP expression, level of both soluble and fibrillar Abeta-peptides, as well as activities of alpha- and beta-secretases in brain slice tissue preparations. Treatment of brain slices with VEGF did not significantly affect the expression level of APP, regardless of the exposure time studied. In contrast, VEGF exposure of brain slices for 6h reduced the formation of soluble, SDS extractable Abeta(1-40) and Abeta(1-42) as compared to brain slice cultures incubated in the absence of any drug, while the fibrillar Abeta peptides did not change significantly. This effect was less pronounced 24h after VEGF exposure, but was no longer detectable when brain slices were exposed by VEGF for 72h, which indicates an adaptive response to chronic VEGF exposure. The VEGF-mediated reduction in Abeta formation was accompanied by a transient decrease in beta-secretase activity peaking 6h after VEGF exposure. To reveal whether the VEGF-induced changes in soluble Abeta-level may be due to actions of VEGF on Abeta fibrillogenesis, the fibrillar status of Abeta was examined using the thioflavin-T binding assay. Incubation of Abeta preparations obtained from Tg2576 Mouse brain cortex, in the presence of VEGF slightly decreased the fibrillar content with increasing incubation time up to 72h. The data demonstrate that VEGF may affect APP processing, at least in vitro, suggesting a role of VEGF in the pathogenesis of Alzheimer's disease.
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Synaptotagmins in Neurodegeneration
Anatomical record (Hoboken N.J. : 2007), 2009Co-Authors: Gordana Glavan, Reinhard Schliebs, Marko ŽivinAbstract:Synaptotagmins (Syts) are transmembrane proteins involved in the regulation of membrane trafficking. Here, we summarize literature data that provide growing evidence that several Syts are involved in the pathophysiological mechanisms of temporal lobe epilepsy and Parkinson's disease, as well as few reports related to brain ischemia and Alzheimer's disease (AD). We also report new data from our laboratories, showing changes of the expression of several Syts in Tg2576 Mouse model of AD that may be related to neuroinflammation surrounding the β-amyloid plaques. Furthermore, we demonstrate N-methyl-D-aspartate receptor-mediated upregulation of Syt 4 mRNA in a model of excitotoxic striatal lesion induced by unilateral striatal injection of quinolinic acid, associating the upregulation of Syt 4 with mechanisms of excitotoxicity. We propose that phamacological manipulation of Syt expression in animal models of neurodegeneration should be further explored, as it may help to clarify the role of individual Syt isoforms in the regulation of membrane trafficking in neurodegeneration. Anat Rec, 292:1849–1862, 2009. © 2009 Wiley-Liss, Inc.
Jenny Apelt - One of the best experts on this subject based on the ideXlab platform.
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alterations in cholinergic and non cholinergic neurotransmitter receptor densities in transgenic Tg2576 Mouse brain with β amyloid plaque pathology
International Journal of Developmental Neuroscience, 2003Co-Authors: Margrit Klingner, Jenny Apelt, Dietlind Sorger, Osama Sabri, Jörg Steinbach, Matthias Scheunemann, Ashok Kumar, Reinhard SchliebsAbstract:Abstract Cholinergic deficits in Alzheimer’s disease are accompanied by a number of alterations in other transmitter systems including glutamate, noradrenaline and serotonin, suggesting the involvement also of other neurotransmitter systems in the pathogenesis of the disease. To address the question whether β-amyloid may contribute to these deficits, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages of 5 (still no significant plaque load) and 17 months (moderate to high cortical β-amyloid plaque load) were examined for a number of cholinergic and non-cholinergic markers. Transgenic mice with no significant plaque load demonstrated reduced hemicholinium-3 (HCh-3) binding to choline uptake sites in anterior brain regions as compared to non-transgenic littermates, while in aged transgenic mice with high number of plaque deposits decreased HCh-3 binding levels were accompanied by increased vesicular acetylcholine transporter binding in selected cortical brain regions. In aged transgenic mice GABA A , NMDA, AMPA, kainate, and β-adrenergic as well 5-HT 1A - and 5-HT 2A -receptor binding levels were hardly affected, whereas α 1 - and α 2 -adrenoceptor binding was increased in selected cerebral cortical regions as compared to non-transgenic littermates. The development of changes in both cholinergic and non-cholinergic markers in transgenic Tg2576 Mouse brain already before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble β-amyloid on cortical neurotransmission and may be referred to the deficits in learning and memory observed in these mice also before significant plaque load.
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Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 Mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein.
Brain research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:To address the question of whether beta-amyloid peptides also affect cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic cholinergic receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical beta-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic cholinergic receptors were observed, which were still reduced in 17-month-old transgenic Mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic cholinergic receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic cholinergic receptor binding was detected in 17-month-old transgenic mice. The development of changes in cholinergic synaptic markers in transgenic Tg2576 Mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
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Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 Mouse brain expressing the Swedish mutation of human β-amyloid precursor protein
Brain Research, 2002Co-Authors: Jenny Apelt, Ashok Kumar, Reinhard SchliebsAbstract:Abstract To address the question of whether β-amyloid peptides also affect cholinergic neurotransmission in vivo, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages ranging from 7 to 24 months were examined by immuno- and histochemical staining for choline acetyltransferase (ChAT) and acetycholinesterase (AChE), by assaying cholinergic enzyme activities and high-affinity choline uptake as well muscarinic and nicotinic cholinergic receptor binding levels by quantitative autoradiography. Cortical and hippocampal activities of AChE and ChAT were not different between transgenic mice and non-transgenic littermates regardless of the postnatal ages examined. However, high-affinity choline uptake was reduced in the hippocampus of 21-month-old transgenic mice. In brains of 8-month-old transgenic mice which do not yet demonstrate cortical β-amyloids, reduced binding levels of cortical and hippocampal M1-muscarinic cholinergic receptors were observed, which were still reduced in 17-month-old transgenic Mouse brains with high plaque load as compared to non-transgenic littermates. M2-muscarinic cholinergic receptor binding was hardly affected in brains from 8-month-old transgenic mice, but in 17-month-old transgenic mice reduced cortical and hippocampal binding levels were observed as compared to non-transgenic controls. Decreased cortical nicotinic cholinergic receptor binding was detected in 17-month-old transgenic mice. The development of changes in cholinergic synaptic markers in transgenic Tg2576 Mouse brain before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble β-amyloid on cholinergic neurotransmission and may be referred to the deficits in learning and memory also observed in these mice before significant plaque load.
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Expression of β-secretase mRNA in transgenic Tg2576 Mouse brain with Alzheimer plaque pathology
Neuroscience letters, 2000Co-Authors: Marina Bigl, Jenny Apelt, E.a Luschekina, C. Lange-dohna, Steffen Roßner, Reinhard SchliebsAbstract:On the basis of the recent cloning of the β-secretase, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), (Science, 286 (1999) 735), digoxigenin-labelled riboprobes were generated to localize the cellular expression pattern of BACE mRNA in brain sections of transgenic Tg2576 mice, overexpressing the Swedish mutation of the APP695 isoform. Non-radioactive in situ hybridization in combination with immunohistochemistry to identify the cell types and β-amyloid deposits revealed strong BACE mRNA hybridization signals in neurons of the cerebral cortex, hippocampal formation, thalamus and cholinergic basal forebrain nuclei, while astrocytes did not display any labeling. Neurons surrounding β-amyloid deposits did not demonstrate altered expression level of BACE mRNA as compared to neurons in cortical areas that are free of β-amyloid deposits, and the regional expression pattern of BACE mRNA did not correlate with the distribution of β-amyloid deposits. These data suggest that high level of expression of BACE mRNA is not necessarily related to enhanced deposition of β-amyloid plaques. To elucidate those factors that contribute to β-amyloid plaque deposition in a particular region, the transgenic Tg2576 Mouse may represent an appropriate tool.
Helen E. Scharfman - One of the best experts on this subject based on the ideXlab platform.
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Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a Mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine
Neurobiology of disease, 2021Co-Authors: David Alcantara-gonzalez, Elissavet Chartampila, Chiara Criscuolo, Helen E. ScharfmanAbstract:Abstract It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer's disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 Mouse, where it has been shown that hyperexcitability is robust at 2–3 months of age. GCs from 2 to 3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward NMDA receptor-dependent current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 Mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG contributes to hyperexcitability and there is cholinergic dysfunction early in life in AD Mouse models.
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Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a Mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine.
2020Co-Authors: David Alcantara-gonzalez, Elissavet Chartampila, Helen E. ScharfmanAbstract:It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer9s disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 Mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 Mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD Mouse models.
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Interictal spikes during sleep are an early defect in the Tg2576 Mouse model of β-amyloid neuropathology.
Scientific reports, 2016Co-Authors: Korey Kam, Aine M. Duffy, Jillian N Moretto, John Lafrancois, Helen E. ScharfmanAbstract:It has been suggested that neuronal hyperexcitability contributes to Alzheimer’s disease (AD), so we asked how hyperexcitability develops in a common Mouse model of β-amyloid neuropathology - Tg2576 mice. Using video-EEG recordings, we found synchronized, large amplitude potentials resembling interictal spikes (IIS) in epilepsy at just 5 weeks of age, long before memory impairments or β-amyloid deposition. Seizures were not detected, but they did occur later in life, suggesting that IIS are possibly the earliest stage of hyperexcitability. Interestingly, IIS primarily occurred during rapid-eye movement (REM) sleep, which is notable because REM is associated with increased cholinergic tone and cholinergic impairments are implicated in AD. Although previous studies suggest that cholinergic antagonists would worsen pathophysiology, the muscarinic antagonist atropine reduced IIS frequency. In addition, we found IIS occurred in APP51 mice which overexpress wild type (WT)-APP, although not as uniformly or as early in life as Tg2576 mice. Taken together with results from prior studies, the data suggest that surprising and multiple mechanisms contribute to hyperexcitability. The data also suggest that IIS may be a biomarker for early detection of AD.
Roberto Cappai - One of the best experts on this subject based on the ideXlab platform.
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a serial analysis of gene expression profile of the alzheimer s disease Tg2576 Mouse model
Neurotoxicity Research, 2010Co-Authors: Amee J George, R Damian M Holsinger, Tim Beissbarth, Irene Koukoulas, Victoria Perreau, Lavinia Gordon, Roberto CappaiAbstract:Serial analysis of gene expression (SAGE), a technique that allows for the simultaneous detection of expression levels of the entire genome without a priori knowledge of gene sequences, was used to examine the transcriptional expression pattern of the Tg2576 Mouse model of Alzheimer’s disease (AD). Pairwise comparison between the Tg2576 and nontransgenic SAGE libraries identified a number of differentially expressed genes in the Tg2576 SAGE library, some of which were not previously revealed by the microarray studies. Real-time PCR was used to validate a panel of genes selected from the SAGE analysis in the Tg2576 Mouse brain, as well as the hippocampus and temporal cortex of sporadic AD and normal age-matched controls. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 5 (NDUFA5) and FXYD domain-containing ion transport regulator 6 (FXYD6) were found to be significantly decreased in the Tg2576 Mouse brain and AD hippocampus. PTEN-induced putative kinase 1 (PINK1), phosphatidylethanolamine binding protein (PEBP), crystalline μ (CRYM), and neurogranin (NRGN) were significantly decreased in AD tissues. The gene ontologies represented in the Tg2576 data were statistically analyzed and demonstrated a significant under-representation of genes involved with G-protein-coupled receptor signaling and odorant binding, while genes significantly over-represented were focused on cellular communication and cellular physiological processes. The novel approach of profiling the Tg2576 Mouse brain using SAGE has identified different genes that could subsequently be examined for their potential as peripheral diagnostic and prognostic markers for Alzheimer’s disease.
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decreased phosphatidylethanolamine binding protein expression correlates with aβ accumulation in the Tg2576 Mouse model of alzheimer s disease
Neurobiology of Aging, 2006Co-Authors: Amee J George, R Damian M Holsinger, Tina Cardamone, Hamish S. Scott, Roberto Cappai, Catriona McleanAbstract:Phosphatidylethanolamine binding protein (PEBP) is a multifunctional protein, with proposed roles as the precursor protein of hippocampal cholinergic neurostimulating peptide (HCNP), and as the Raf kinase inhibitor protein (RKIP). Previous studies have demonstrated a decrease in PEBP mRNA in CA1 region of AD hippocampus. The current study demonstrates that PEBP is decreased in the hippocampus of 11 month Tg2576 mice, in the absence of change in mRNA levels compared to non-transgenic littermates. The level of PEBP in transgenic Mouse hippocampus significantly decreases at 11 months (a time point when Aβ begins accumulating) and 15 months (when Aβ plaques have formed). There was a significant correlation between decreased PEBP expression and accumulation of Aβ. Immunohistochemical studies on Tg2576 and AD brain sections demonstrate that PEBP immunoreactivities are present at the periphery of dense multicore Aβ plaques, and in selective astrocytes, primarily surrounding plaques. These findings suggest that PEBP expression may be influenced by accumulation of Aβ. Down-regulation of PEBP may result in lower levels of HCNP or altered coordination of signal transduction pathways that may contribute to neuronal dysfunction and pathogenesis in AD.
Steffen Roßner - One of the best experts on this subject based on the ideXlab platform.
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Cell Type-Specific Human APP Transgene Expression by Hippocampal Interneurons in the Tg2576 Mouse Model of Alzheimer's Disease.
Frontiers in neuroscience, 2019Co-Authors: Corinna Höfling, Peer-hendrik Kuhn, Stefan F. Lichtenthaler, Maike Hartlage-rübsamen, Emira Shehabi, Steffen RoßnerAbstract:Amyloid precursor protein (APP) transgenic animal models of Alzheimer's disease have become versatile tools for basic and translational research. However, there is great heterogeneity of histological, biochemical, and functional data between transgenic Mouse lines, which might be due to different transgene expression patterns. Here, the expression of human APP (hAPP) by GABAergic hippocampal interneurons immunoreactive for the calcium binding proteins parvalbumin, calbindin, calretinin, and for the peptide hormone somatostatin was analyzed in Tg2576 mice by double immunofluorescent microscopy. Overall, there was no GABAergic interneuron subpopulation that did not express the transgene. On the other hand, in no case all neurons of such a subpopulation expressed hAPP. In dentate gyrus molecular layer and in stratum lacunosum moleculare less than 10% of hAPP-positive interneurons co-express any of these interneuron markers, whereas in stratum oriens hAPP-expressing neurons frequently co-express these interneuron markers to different proportions. We conclude that these neurons differentially contribute to deficits in young Tg2576 mice before the onset of Abeta plaque pathology. The detailed analysis of distinct brain region and neuron type-specific APP transgene expression patterns is indispensable to understand particular pathological features and Mouse line-specific differences in neuronal and systemic functions.
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Cell Type-Specific Human APP Transgene Expression by Hippocampal Interneurons in the Tg2576 Mouse Model of Alzheimer’s Disease
Frontiers Media S.A., 2019Co-Authors: Corinna Höfling, Peer-hendrik Kuhn, Stefan F. Lichtenthaler, Maike Hartlage-rübsamen, Emira Shehabi, Steffen RoßnerAbstract:Amyloid precursor protein (APP) transgenic animal models of Alzheimer’s disease have become versatile tools for basic and translational research. However, there is great heterogeneity of histological, biochemical, and functional data between transgenic Mouse lines, which might be due to different transgene expression patterns. Here, the expression of human APP (hAPP) by GABAergic hippocampal interneurons immunoreactive for the calcium binding proteins parvalbumin, calbindin, calretinin, and for the peptide hormone somatostatin was analyzed in Tg2576 mice by double immunofluorescent microscopy. Overall, there was no GABAergic interneuron subpopulation that did not express the transgene. On the other hand, in no case all neurons of such a subpopulation expressed hAPP. In dentate gyrus molecular layer and in stratum lacunosum moleculare less than 10% of hAPP-positive interneurons co-express any of these interneuron markers, whereas in stratum oriens hAPP-expressing neurons frequently co-express these interneuron markers to different proportions. We conclude that these neurons differentially contribute to deficits in young Tg2576 mice before the onset of Abeta plaque pathology. The detailed analysis of distinct brain region and neuron type-specific APP transgene expression patterns is indispensable to understand particular pathological features and Mouse line-specific differences in neuronal and systemic functions
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Defined astrocytic expression of human amyloid precursor protein in Tg2576 Mouse brain.
Glia, 2018Co-Authors: Tina Heiland, Steffen Roßner, Ulrike Zeitschel, Maja Puchades, Peer-hendrik Kuhn, Stefan F. Lichtenthaler, Jan G. Bjaalie, Maike Hartlage-rübsamen, Corinna HöflingAbstract:Transgenic Tg2576 mice expressing human amyloid precursor protein (hAPP) with the Swedish mutation are among the most frequently used animal models to study the amyloid pathology related to Alzheimer's disease (AD). The transgene expression in this model is considered to be neuron-specific. Using a novel hAPP-specific antibody in combination with cell type-specific markers for double immunofluorescent labelings and laser scanning microscopy, we here report that-in addition to neurons throughout the brain-astrocytes in the corpus callosum and to a lesser extent in neocortex express hAPP. This astrocytic hAPP expression is already detectable in young Tg2576 mice before the onset of amyloid pathology and still present in aged Tg2576 mice with robust amyloid pathology in neocortex, hippocampus, and corpus callosum. Surprisingly, hAPP immunoreactivity in cortex is restricted to resting astrocytes distant from amyloid plaques but absent from reactive astrocytes in close proximity to amyloid plaques. In contrast, neither microglial cells nor oligodendrocytes of young or aged Tg2576 mice display hAPP labeling. The astrocytic expression of hAPP is substantiated by the analyses of hAPP mRNA and protein expression in primary cultures derived from Tg2576 offspring. We conclude that astrocytes, in particular in corpus callosum, may contribute to amyloid pathology in Tg2576 mice and thus mimic this aspect of AD pathology.
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Expression of β-secretase mRNA in transgenic Tg2576 Mouse brain with Alzheimer plaque pathology
Neuroscience letters, 2000Co-Authors: Marina Bigl, Jenny Apelt, E.a Luschekina, C. Lange-dohna, Steffen Roßner, Reinhard SchliebsAbstract:On the basis of the recent cloning of the β-secretase, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), (Science, 286 (1999) 735), digoxigenin-labelled riboprobes were generated to localize the cellular expression pattern of BACE mRNA in brain sections of transgenic Tg2576 mice, overexpressing the Swedish mutation of the APP695 isoform. Non-radioactive in situ hybridization in combination with immunohistochemistry to identify the cell types and β-amyloid deposits revealed strong BACE mRNA hybridization signals in neurons of the cerebral cortex, hippocampal formation, thalamus and cholinergic basal forebrain nuclei, while astrocytes did not display any labeling. Neurons surrounding β-amyloid deposits did not demonstrate altered expression level of BACE mRNA as compared to neurons in cortical areas that are free of β-amyloid deposits, and the regional expression pattern of BACE mRNA did not correlate with the distribution of β-amyloid deposits. These data suggest that high level of expression of BACE mRNA is not necessarily related to enhanced deposition of β-amyloid plaques. To elucidate those factors that contribute to β-amyloid plaque deposition in a particular region, the transgenic Tg2576 Mouse may represent an appropriate tool.