40 results on '"Bayer, Thomas A."'
Search Results
2. Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer’s disease
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Kumar, Sathish, Wirths, Oliver, Theil, Sandra, Gerth, Janina, Bayer, Thomas A., and Walter, Jochen
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- 2013
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3. Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases
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Wirths, Oliver, Bethge, Tobias, Marcello, Andrea, Harmeier, Anja, Jawhar, Sadim, Lucassen, Paul J., Multhaup, Gerd, Brody, David L., Esparza, Thomas, Ingelsson, Martin, Kalimo, Hannu, Lannfelt, Lars, and Bayer, Thomas A.
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- 2010
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4. Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice
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Christensen, Ditte Zerlang, Kraus, Sophie Luise, Flohr, Antonius, Cotel, Marie-Caroline, Wirths, Oliver, and Bayer, Thomas A.
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- 2008
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5. Copper and clioquinol treatment in young APP transgenic and wild-type mice: effects on life expectancy, body weight, and metal-ion levels
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Schäfer, Stephanie, Pajonk, Frank-Gerald, Multhaup, Gerd, and Bayer, Thomas A.
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- 2007
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6. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease
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Wirths, Oliver, Weis, Joachim, Szczygielski, Jacek, Multhaup, Gerd, and Bayer, Thomas A.
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- 2006
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7. Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease
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Wagner, Jannek M., Sichler, Marius E., Schleicher, Eva M., Franke, Timon N., Irwin, Caroline, Löw, Maximilian Johannes, Beindorff, Nicola, Bouter, Caroline, Bayer, Thomas A., and Bouter, Yvonne
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cerebellum ,behavior ,Cognitive Neuroscience ,motor function ,transgenic mice ,lcsh:RC321-571 ,Behavioral Neuroscience ,Neuropsychology and Physiological Psychology ,Alzheimer ,FDG-PET ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neuroscience ,Original Research - Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia. Hallmarks of AD are memory impairments and cognitive deficits, but non-cognitive impairments, especially motor dysfunctions are also associated with the disease and may even precede classic clinical symptoms. With an aging society and increasing hospitalization of the elderly, motor deficits are of major interest to improve independent activities in daily living. Consistent with clinical findings, a variety of AD mouse models develop motor deficits as well. We investigated the motor function of 3- and 7-month-old Tg4-42 mice in comparison to wild-type controls and 5XFAD mice and discuss the results in context with several other AD mouse model. Our study shows impaired balance and motor coordination in aged Tg4-42 mice in the balance beam and rotarod test, while general locomotor activity and muscle strength is not impaired at 7 months. The cerebellum is a major player in the regulation and coordination of balance and locomotion through practice. Particularly, the rotarod test is able to detect cerebellar deficits. Furthermore, supposed cerebellar impairment was verified by 18F-FDG PET/MRI. Aged Tg4-42 mice showed reduced cerebellar glucose metabolism in the 18F-FDG PET. Suggesting that, deficits in coordination and balance are most likely due to cerebellar impairment. In conclusion, Tg4-42 mice develop motor deficits before memory deficits, without confounding memory test. Thus, making the Tg4-42 mouse model a good model to study the effects on cognitive decline of therapies targeting motor impairments. Open-Access-Publikationsfonds 2019 peerReviewed
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- 2019
8. Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease
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Hullmann, Maja, Albrecht, Catrin, van Berlo, Damiën, Gerlofs-Nijland, Miriam E, Wahle, Tina, Boots, Agnes W, Krutmann, Jean, Cassee, Flemming R, Bayer, Thomas A, Schins, Roel P F, LS IRAS EEPI Inhalatie Toxicologie, dIRAS RA-1, LS IRAS EEPI Inhalatie Toxicologie, dIRAS RA-1, Farmacologie en Toxicologie, RS: NUTRIM - R3 - Respiratory & Age-related Health, and RS: NUTRIM - R4 - Gene-environment interaction
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0301 basic medicine ,Pathology ,Health, Toxicology and Mutagenesis ,Physiology ,Plaque, Amyloid ,Toxicology ,Systemic inflammation ,NEURON LOSS ,0302 clinical medicine ,11. Sustainability ,BRAIN ,5XFAD mice ,Vehicle Emissions ,TRANSGENIC MICE ,Inhalation exposure ,Air Pollutants ,Inhalation Exposure ,Inhalation ,biology ,Behavior, Animal ,Chemistry ,General Medicine ,Amyloid-ß ,Alzheimer's disease ,3. Good health ,AMYLOID PRECURSOR PROTEIN ,medicine.anatomical_structure ,Memory, Short-Term ,Female ,Amyloid-beta ,medicine.symptom ,Alzheimer’s disease ,Genetically modified mouse ,medicine.medical_specialty ,Amyloid beta ,Central nervous system ,lcsh:Industrial hygiene. Industrial welfare ,Inflammation ,Mice, Inbred Strains ,03 medical and health sciences ,INFLAMMATION ,lcsh:RA1190-1270 ,Alzheimer Disease ,medicine ,PARTICLES ,Animals ,Amyloid-β ,Behaviour ,lcsh:Toxicology. Poisons ,Research ,Diesel engine exhaust ,AIR-POLLUTION ,COGNITIVE FUNCTION ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,SUBCHRONIC EXPOSURE ,13. Climate action ,biology.protein ,Particulate Matter ,Particulate matter ,030217 neurology & neurosurgery ,lcsh:HD7260-7780.8 - Abstract
Background Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer’s Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m3, 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-β (Aβ) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. Results In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aβ plaque load and higher whole brain homogenate Aβ42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. Conclusions Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer’s disease.
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- 2017
9. Transgene integration causes RARB downregulation in homozygous Tg4–42 mice.
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Hinteregger, Barbara, Loeffler, Tina, Flunkert, Stefanie, Neddens, Joerg, Birner-Gruenberger, Ruth, Bayer, Thomas A., Madl, Tobias, and Hutter-Paier, Birgit
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TRANSGENES ,DOWNREGULATION ,ALZHEIMER'S disease ,TRANSGENIC mice ,TRETINOIN - Abstract
Alzheimer's disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4–42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further caused a deletion of exon 2 of the retinoic acid receptor beta. These findings were also confirmed on protein level with highly decreased retinoic acid receptor beta protein levels in homozygous Tg4–42 mice and may have an impact on the previously described phenotype of homozygous Tg4–42 mice to be solely dependent on amyloid-ß 4–42 expression. Since hemizygous mice show no changes in RARB protein levels it can be concluded that the previously described phenotype of these mice should not be affected by the retinoic acid receptor beta gene knockout. In order to fully understand the results of transgenesis, it is extremely advisable to determine the genome integration site and the basic structure of the inserted transgenes. This can be carried out for instance by next-generation sequencing techniques. Our results thus suggest that a detailed characterization of new disease models using the latest genomics technologies prior to functional studies could be a valuable tool to avoid an unexpected genetic influence on the animals' phenotype that is not only based on the inserted transgene. This would also significantly improve the selection of mouse models that are best suited for therapeutic development and basic research. [ABSTRACT FROM AUTHOR]
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- 2020
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10. Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer’s disease and transgenic mouse models
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Reinert, Jochim, Richard, Bernhard C., Klafki, Hans W., Friedrich, Beate, Bayer, Thomas A., Wiltfang, Jens, Kovacs, Gabor G., Ingelsson, Martin, Lannfelt, Lars, Paetau, Anders, Bergquist, Jonas, and Wirths, Oliver
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Male ,Aβ37 ,Mice, Transgenic ,C-terminal truncation ,Amyloid beta-Protein Precursor ,Mice ,Alzheimer Disease ,Presenilin-1 ,Transgenic mice ,Animals ,Humans ,Aged ,Aged, 80 and over ,Amyloid beta-Peptides ,Mass spectrometry ,Research ,Age Factors ,Brain ,Middle Aged ,Immunohistochemistry ,Peptide Fragments ,Mice, Inbred C57BL ,Disease Models, Animal ,Gene Expression Regulation ,Amyloid precursor protein ,Mutation ,Alzheimer ,Female ,Down Syndrome ,Aβ39 - Abstract
In Alzheimer’s disease (AD) a variety of amyloid β-peptides (Aβ) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Aβ from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by β- and γ-secretases. Brain accumulation of Aβ due to impaired Aβ degradation and/or altered ratios between the different Aβ species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Aβ40 and Aβ42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Aβ peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Aβ37 and Aβ39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 ΔExon9 mutation. Aβ37 and Aβ39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Aβ37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Aβ in sporadic and familial AD and raises questions about how these species are generated and regulated. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0294-7) contains supplementary material, which is available to authorized users.
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- 2016
11. Deposition of C-terminally truncated A beta species A beta 37 and A beta 39 in Alzheimer's disease and transgenic mouse models
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Reinert, Jochim, Richard, Bernhard C., Klafki, Hans W., Friedrich, Beate, Bayer, Thomas A., Wiltfang, Jens, Kovacs, Gabor G., Ingelsson, Martin, Lannfelt, Lars, Paetau, Anders, Bergquist, Jonas, Wirths, Oliver, Medicum, Department of Pathology, Clinicum, and University of Helsinki
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Mass spectrometry ,Neurologi ,MUTATIONS ,3112 Neurosciences ,A beta 37 ,PEPTIDES ,A-BETA(42) ,A beta 39 ,C-terminal truncation ,Immunohistochemistry ,AMYLOID PRECURSOR PROTEIN ,MICE ,CEREBROSPINAL-FLUID ,Neurology ,Amyloid precursor protein ,GAMMA-SECRETASE ACTIVITY ,PLAQUE CORE ,Alzheimer ,Transgenic mice ,APP ,GENERATION - Abstract
In Alzheimer's disease (AD) a variety of amyloid beta-peptides (A beta) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of A beta from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by beta-and gamma-secretases. Brain accumulation of A beta due to impaired A beta degradation and/or altered ratios between the different A beta species produced is believed to play a pivotal role in AD pathogenesis. While the presence of A beta 40 and A beta 42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated A beta peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of A beta 37 and A beta 39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 Delta Exon9 mutation. A beta 37 and A beta 39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of A beta 37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated A beta in sporadic and familial AD and raises questions about how these species are generated and regulated.
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- 2016
12. N-Terminal Truncated Aβ4-42 Is a Substrate for Neprilysin Degradation in vitro and in vivo.
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Hornung, Karen, Zampar, Silvia, Engel, Nadine, Klafki, Hans, Liepold, Thomas, Bayer, Thomas A., Wiltfang, Jens, Jahn, Olaf, and Wirths, Oliver
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NEPRILYSIN ,ALZHEIMER'S disease ,MASS spectrometry ,TRANSGENIC mice ,PEPTIDES ,AMYLOID ,ANIMAL experimentation ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,NEURONS ,PROTEOLYTIC enzymes ,RESEARCH ,EVALUATION research - Abstract
In sporadic Alzheimer's disease (AD), an imbalance between production and clearance of amyloid-β (Aβ) peptides seems to account for enhanced Aβ accumulation. The metalloprotease neprilysin (NEP) is an important Aβ degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aβ peptides such as Aβ1-40 and Aβ1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aβ species such as the common variant Aβ4-42. In the present report, we confirmed the degradation of Aβ4-x species by neprilysin using in vitro digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aβ4-42 peptides with homozygous NEP-knock-out mice (NEP-/-), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aβ levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Gene Expression Profiling in the APP/PS1KI Mouse Model of Familial Alzheimer's Disease.
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Weissmann, Robert, Hüttenrauch, Melanie, Kacprowski, Tim, Bouter, Yvonne, Pradier, Laurent, Bayer, Thomas A., Kuss, Andreas W., and Wirths, Oliver
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ALZHEIMER'S disease ,AMYLOID ,GENE expression ,NEXT generation networks ,TRANSGENIC animals ,BRAIN metabolism ,ANIMAL experimentation ,ANIMALS ,BIOLOGICAL models ,BRAIN ,MEMBRANE proteins ,MICE ,NEURODEGENERATION ,PROTEIN precursors ,GENE expression profiling - Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses. [ABSTRACT FROM AUTHOR]
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- 2016
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14. Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease.
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Richard, Bernhard Clemens, Kurdakova, Anastasiia, Baches, Sandra, Bayer, Thomas A., Weggen, Sascha, and Wirths, Oliver
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ALZHEIMER'S disease research ,AMYLOID ,SPATIAL memory ,TRANSGENIC mice ,NEUROLOGICAL disorders - Abstract
In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research. [ABSTRACT FROM AUTHOR]
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- 2015
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15. Neprilysin Deficiency Alters the Neuropathological and Behavioral Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease.
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Hüttenrauch, Melanie, Baches, Sandra, Gerth, Janina, Bayer, Thomas A., Weggen, Sascha, and Wirths, Oliver
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NEPRILYSIN ,METALLOPROTEINASES ,ALZHEIMER'S disease ,BASAL ganglia diseases ,PRESENILE dementia - Abstract
The deposition of amyloid-β (Aβ) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). In the case of sporadic AD, an imbalance in Aβ in production and clearance seems to be the reason for an enhanced Aβ accumulation. Besides a systematic clearance through the blood-brain barrier, Aβ is cleared from the brain by Aβ-degrading enzymes. The metalloprotease neprilysin (NEP) is an important Aβ-degrading enzyme as shown by numerous in vitro, in vivo and reverse genetics studies. 5XFAD mice represent an early-onset AD mouse model which develops plaque pathology starting with 2 months of age in addition to robust behavioral deficits at later time points. By crossing 5XFAD mice with homozygous NEP-knock-out mice (NEP-/-), we show that hemizygous NEP deficiency aggravates the behavioral and neuropathological phenotype of 5XFAD mice. We found that 5XFAD mice per se showed strongly decreased NEP expression levels compared to wildtype mice, which was aggravated by NEP reduction. 5XFAD/NEP+/- mice demonstrated impairment in spatial working memory and increased astrocytosis in all studied brain areas, in addition to an overall increased level of soluble Aβ42 as well as region-specific increases in extracellular Aβ deposition. Surprisingly, in young mice, a more abundant cortical Aβ plaque pathology was observed in 5XFAD compared to 5XFAD/NEP+/- mice. Additionally, young 5XFAD/NEP+/- as well as hemi- and homozygous NEP knockout mice showed elevated levels of endothelin-converting enzyme 1 (ECE1), suggesting a mutual regulation of ECE1 and NEP at young ages. The present data indicate that NEP mainly degrades soluble Aβ peptides, which confirms previous observations. Increased ECE1 levels correlated well with the strongly reduced extracellular plaque load in young 5XFAD/NEP+/- mice and might suggest a reciprocal effect between ECE and NEP activities in Aβ degradation. [ABSTRACT FROM AUTHOR]
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- 2015
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16. Aβ38 in the Brains of Patients with Sporadic and Familial Alzheimer's Disease and Transgenic Mouse Models.
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Reinert, Jochim, Martens, Henrik, Huettenrauch, Melanie, Kolbow, Tekla, Lannfelt, Lars, Ingelsson, Martin, Paetau, Anders, Verkkoniemi-Ahola, Auli, Bayer, Thomas A., and Wirths, Oliver
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ALZHEIMER'S disease research ,AMYLOID beta-protein precursor ,NEUROTOXICOLOGY ,PRESENILINS ,CENTRAL nervous system ,TRANSGENIC mice - Abstract
The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-β peptides (Aβ), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aβ peptides existing are generated by subsequent cleavage of the amyloid-β protein precursor (AβPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aβ40 and Aβ42, Aβ peptides with other C-termini such as Aβ38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aβ38 to analyze the distribution of this Aβ species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aβ38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aβ38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aβ38-positive plaques not only among familial cases due to AβPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aβ38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AβPP, or combinations of AβPP, PSEN1, and tau transgenes. [ABSTRACT FROM AUTHOR]
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- 2014
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17. Abundance of Aβ5-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease.
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Avendaño Guzmán, Erika, Bouter, Yvonne, Richard, Bernhard C., Lannfelt, Lars, Ingelsson, Martin, Paetau, Anders, Verkkoniemi-Ahola, Auli, Wirths, Oliver, and Bayer, Thomas A.
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ALZHEIMER'S disease ,DISEASES in older people ,AMYLOID beta-protein precursor ,TRANSGENIC mice ,PROTEIN precursors ,AMYLOID beta-protein ,NEURONS - Abstract
Background According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptide (Aβ) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Aβ
x-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Aβx-42 species have been pointed as crucial players in AD etiology, the Aβ5-x isoforms have not received much attention. Results The present study is the first to show immunohistochemical evidence of Aβ5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Aβ5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Aβ5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Aβ deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Aβ5-x . Conclusions Different degrees of Aβ5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Aβ5-x , these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Aβ5-x -immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Aβ5-x peptides and operating in a divergent way in the late and early onset forms of the disease. [ABSTRACT FROM AUTHOR]- Published
- 2014
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18. N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.
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Bouter, Yvonne, Dietrich, Katharina, Wittnam, Jessica, Rezaei-Ghaleh, Nasrollah, Pillot, Thierry, Papot-Couturier, Sophie, Lefebvre, Thomas, Sprenger, Frederick, Wirths, Oliver, Zweckstetter, Markus, and Bayer, Thomas
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AMYLOID beta-protein ,ALZHEIMER'S disease ,ETIOLOGY of diseases ,NEURONS ,TRANSGENIC mice ,HIPPOCAMPUS (Brain) ,MONOMERS ,OLIGOMERS - Abstract
N-truncated Aβ is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ is as toxic as pyroglutamate Aβ and Aβ. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ, pyroglutamate Aβ and Aβ. Transgenic mice expressing Aβ (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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19. Intraneuronal Aβ accumulation and neurodegeneration: Lessons from transgenic models
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Wirths, Oliver and Bayer, Thomas A.
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NEURODEGENERATION , *ANIMAL models of brain diseases , *ALZHEIMER'S disease , *NEURONS , *IMMUNOGLOBULINS , *TRANSGENIC animals - Abstract
Abstract: Aims: In the present review we summarize current knowledge on the concept of intraneuronal Aβ as a determinant for neuron loss and other pathological alterations in transgenic models for Alzheimer disease. Main methods: We discuss the use of transgenic mouse and non-vertebrate transgenic models accumulating intracellular Aβ peptides and their impact on the ongoing discussion. Key findings: Intraneuronal Aβ accumulation in transgenic models is intimately linked to pathological alterations including neuron loss. One of the technical caveats for visualizing intraneuronal Aβ is the antibody used to unequivocally demonstrate its presence. Very often antibodies were used that recognize both Aβ and APP, leading to false positive results due to misinterpretation. Significance: Whereas a clear relationship between intraneuronal Aβ accumulation and neuron loss is evident in transgenic mouse models it remains an unresolved issue whether the concept of intraneuronal Aβ can be integrated into the human pathology as well. [Copyright &y& Elsevier]
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- 2012
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20. AβPP Accumulation and/or Intraneuronal Amyloid-β Accumulation? The 3xTg-AD Mouse Model Revisited.
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Wirths, Oliver, Dins, Annika, and Bayer, Thomas A.
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AMYLOID beta-protein precursor ,ALZHEIMER'S disease ,IMMUNOHISTOCHEMISTRY ,PYROGLUTAMIC acid ,LABORATORY mice - Abstract
The triple-transgenic Alzheimer's disease (AD) mouse model, 3xTg-AD, played an important role in supporting the intraneuronal amyloid-β (Aβ) hypothesis in AD. However, recent evidence claims that the 3xTg-AD mice accumulate amyloid-β protein precursor (AβPP) instead of Aβ within neurons. In the present report, we re-investigated the 3xTg-AD mouse model and confirmed recent findings of age-dependent AβPP accumulations. In addition, intraneuronal Aβ was detected mainly in the neocortex using conformation-specific as well as antibodies directed against Aβ neo-epitopes. In contrast to previous work, however, only minor levels of intraneuronal Aβ were detected in the CA1 region of the hippocampus in aged 3xTg-AD mice. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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21. Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease
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Christensen, Ditte Z., Bayer, Thomas A., and Wirths, Oliver
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CHOLINERGIC mechanisms , *PARASYMPATHOMIMETIC agents , *ALZHEIMER'S patients , *TRANSGENE expression , *PROSENCEPHALON , *CELL death , *ACETYLCHOLINE , *LABORATORY mice - Abstract
Abstract: Loss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer''s disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined Aβ-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular Aβ accumulation, whereas no APP expressing neurons and thus no intracellular Aβ accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular Aβ accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular Aβ. This study supports the hypothesis of intracellular Aβ accumulation as an early pathological alteration contributing to cell death in AD. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
22. Accumulation of intraneuronal Aβ correlates with ApoE4 genotype.
- Author
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Christensen, Ditte Z., Schneider-Axmann, Thomas, Lucassen, Paul J., Bayer, Thomas A., and Wirths, Oliver
- Subjects
ALZHEIMER'S disease ,BRAIN diseases ,TRANSGENIC mice ,GENETIC polymorphisms ,STAINS & staining (Microscopy) - Abstract
In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
23. Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Aβ peptides in mouse models of Alzheimer's disease
- Author
-
Christensen, Ditte Z., Bayer, Thomas A., and Wirths, Oliver
- Subjects
- *
FORMIC acid , *IMMUNOHISTOCHEMISTRY , *PEPTIDES , *ALZHEIMER'S disease , *ANTIGENS , *MICROWAVE heating , *LABORATORY mice , *AMYLOID beta-protein - Abstract
Abstract: The staining protocols so far applied to study intracellular Aβ accumulation in human tissue have been inconsistent with varying use of heat and formic acid (FA) for antigen retrieval. Microwave heat treatment has been reported to enhance the staining of intraneuronal Aβ as compared to no or enzymatic pretreatment. FA is widely used to increase the staining of plaque pathology in AD, yet the effect of FA on intraneuronal Aβ staining has been reported to be low and similar to the effect of heat or even to counteract the enhancing effect of heat pretreatment on intraneuronal Aβ immunohistochemical detection. To overcome these inconsistencies, there is a need for optimization of the staining protocol for intraneuronal Aβ detection and more knowledge is required concerning the effects of the different antigen retrieval methods. In the present work, we optimized the staining protocol for intraneuronal Aβ in paraffin-embedded sections in relation to heat and FA using four different mouse models known to accumulate intraneuronal Aβ peptides. It was found that FA is essential for the staining of highly aggregated intraneuronal Aβ peptides in AD transgenic mouse tissue. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
24. Age-dependent loss of dentate gyrus granule cells in APP/PS1KI mice
- Author
-
Cotel, Marie-Caroline, Bayer, Thomas A., and Wirths, Oliver
- Subjects
- *
DENTATE gyrus , *HIPPOCAMPUS (Brain) , *ALZHEIMER'S disease , *MICE - Abstract
Abstract: Loss of neurons in the hippocampus and other brain regions is, besides the occurrence of plaques and tangles, a neuropathological feature of Alzheimer''s disease (AD). In recent years a plethora of transgenic mouse models overexpressing mutant amyloid precursor protein (APP) has been developed, which represent valuable research tools. Whereas extracellular plaque pathology is a common feature of these models, neuronal loss is a rather rare characteristic. In the present study, we quantified the number of neurons in the dentate gyrus granule layer (GCL) in 2- and 12-month-old APP/PS1KI mice, a mouse model that has been previously shown to have significant loss of neurons in the CA1 layer of the hippocampus. Stereological analysis revealed a strongly significant decrease of GCLs in aged APP/PS1KI mice, compared to age-matched PS1KI control animals (−44%), however, the volume of the GCL was not different. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
25. A modifiedβ-amyloid hypothesis: intraneuronal accumulation of theβ-amyloid peptide– the first step of a fatal cascade.
- Author
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Wirths, Oliver, Multhaup, Gerd, and Bayer, Thomas A.
- Subjects
AMYLOIDOSIS ,NEURODEGENERATION ,DEGENERATION (Pathology) ,AMYLOID beta-protein ,MEMORY disorders ,PERSONALITY disorders ,ALZHEIMER'S disease ,DOWN syndrome - Abstract
Accumulating evidence points to an important role of intraneuronal Aβ as a trigger of the pathological cascade of events leading to neurodegeneration and eventually to Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and change in personality. In the present article, we review recent findings on intracellular monomeric and oligomericβ-amyloid (Aβ) generation and its pathological function in cell culture, transgenic AD mouse models and post mortem brain tissue of AD and Down syndrome patients, as well as its interaction with oxidative stress and its relevance in apoptotic cell death. Based on these results, a modified Aβ hypothesis is formulated, that integrates biochemical, neuropathological and genetic observations with AD-typical neuron loss and plaque formation. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
26. Intraneuronal β-Amyloid Is a Major Risk Factor – Novel Evidence from the APP/PS1KI Mouse Model.
- Author
-
Bayer, Thomas A., Breyhan, Henning, Duan, Kailai, Rettig, Jens, and Wirths, Oliver
- Subjects
- *
AMYLOID , *NEURODEGENERATION , *SHORT-term memory , *NEUROPLASTICITY , *ALZHEIMER'S disease , *TRANSGENIC mice - Abstract
Accumulating evidence points to an important role of intraneuronal β-amyloid (Aβ) in the development of Alzheimer’s disease (AD), with its typical clinical symptoms like memory impairment and changes in personality. We have previously reported on the Aβ precursor protein and presenilin-1 knock-out (APP/PS1KI) mouse model with abundant intraneuronal Aβ42 accumulation and a 50% loss of CA1 neurons at 10 months of age. In addition, we observed reduced short- and long-term synaptic plasticity, hippocampal neuron loss, and reduced performance in a working memory task. These observations support a pivotal role of intraneuronal Aβ accumulation as a principal pathological trigger in AD. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
27. Synaptic Alterations in Mouse Models for Alzheimer Disease—A Special Focus on N-Truncated Abeta 4-42.
- Author
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Dietrich, Katharina, Bouter, Yvonne, Müller, Michael, Bayer, Thomas A., Hutter-Paier, Birgit, and Schilling, Stephan
- Subjects
NEURAL transmission ,ALZHEIMER'S patients ,ELECTROPHYSIOLOGY ,NEUROTOXICOLOGY ,TRANSGENIC mice ,LABORATORY mice - Abstract
This commentary reviews the role of the Alzheimer amyloid peptide Aβ on basal synaptic transmission, synaptic short-term plasticity, as well as short- and long-term potentiation in transgenic mice, with a special focus on N-terminal truncated Aβ
4-42 . Aβ4-42 is highly abundant in the brain of Alzheimer’s disease (AD) patients. It demonstrates increased neurotoxicity compared to full length Aβ, suggesting an important role in the pathogenesis of AD. Transgenic Tg4-42 mice, a model for sporadic AD, express human Aβ4-42 in Cornu Ammonis (CA1) neurons, and develop age-dependent hippocampal neuron loss and neurological deficits. In contrast to other transgenic AD mouse models, the Tg4-42 model exhibits synaptic hyperexcitability, altered synaptic short-term plasticity with no alterations in short- and long-term potentiation. The outcomes of this study are discussed in comparison with controversial results from other AD mouse models. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
28. Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease.
- Author
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Saul, Anika, Sprenger, Frederik, Bayer, Thomas A., and Wirths, Oliver
- Subjects
- *
MEMORY loss , *TRANSGENIC mice , *ALZHEIMER'S disease , *NERVOUS system abnormalities , *AMYLOID beta-protein , *PATHOLOGY , *TAU proteins - Abstract
Abstract: There is pivotal evidence that tau pathology can be triggered by amyloid-β (Aβ) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Aβ aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
29. Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease.
- Author
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Jawhar, Sadim, Wirths, Oliver, and Bayer, Thomas A.
- Subjects
- *
ALZHEIMER'S disease , *AMYLOID beta-protein , *TRANSGENIC mice , *LABORATORY mice , *GLUTAMINYL-peptide cyclotransferase - Abstract
Pyroglutamate-modified amyloid-β (AβpE3) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of AβpE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of AβpE3. In this minireview, we summarize the current knowledge on AβpE3, discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
30. Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.
- Author
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Schuessel, Katrin, Schäfer, Stephanie, Bayer, Thomas A., Czech, Christian, Pradier, Laurent, Müller-Spahn, Franz, Müller, Walter E., and Eckert, Anne
- Subjects
- *
SUPEROXIDE dismutase , *OXIDATIVE stress , *ALZHEIMER'S disease , *AMYLOID beta-protein precursor , *GLUTATHIONE peroxidase , *LIPID peroxidation (Biology) , *TRANSGENIC mice - Abstract
Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease. To determine which mechanisms cause the origin of oxidative damage, we analyzed enzymatic antioxidant defense (Cu/Zn-superoxide dismutase Cu/Zn-SOD, glutathione peroxidase GPx and glutathione reductase GR) and lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE in two different APP transgenic mouse models at 3–4 and 12–15 months of age. No changes in any parameter were observed in brains from PDGF-APP695 SDL mice, which have low levels of Aβ and no plaque load. In contrast, Thy1-APP751 SL mice show high Aβ accumulation with aging and plaques from an age of 6 months. In brains of these mice, HNE levels were increased at 3 months (female transgenic mice) and at 12 months (both gender), that is, before and after plaque deposition, and the activity of Cu/Zn-SOD was reduced. Interestingly, β-amyloidogenic cleavage of APP was increased in female Thy1-APP751 SL mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751 SL mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751 SL transgenic mice, and these findings are closely linked to increased β-amyloidogenic cleavage of APP. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
31. Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease.
- Author
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Wittnam, Jessica L., Portelius, Erik, Zetterberg, Henrik, Gustavsson, Mikael K., Schilling, Stephan, Koch, Birgit, Demuth, Hans-Ulrich, Blennow, Kaj, Wirths, Oliver, and Bayer, Thomas A.
- Subjects
- *
AMINO acids , *ALZHEIMER'S disease , *MASS spectrometry , *ENZYME-linked immunosorbent assay , *TRANSGENIC mice - Abstract
Pyroglutamate-modified Aβ peptides at amino acid position three (AβpE3-42) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). AβpE3-42 is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aβ pE3-42 levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aβ pE3-42 TBA42 mice showed age-dependent behavioral deficits and Aβ pE3-42 accumulation. The Aβ profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aβ peptides: Aβ1-42, Aβ1-40, Aβ pE3-42, Aβ pE3-42 Aβ pE3-42, Aβ 4-42, and Aβ 5-42 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed thatAβpE3 levels were elevated in FAD42 mice. No change in Aβ x-42 or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aβ pE3-42in FAD42 mice. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
32. Environmental enrichment fails to rescue working memory deficits, neuron loss, and neurogenesis in APP/PS1KI mice
- Author
-
Cotel, Marie-Caroline, Jawhar, Sadim, Christensen, Ditte Z., Bayer, Thomas A., and Wirths, Oliver
- Subjects
- *
DEVELOPMENTAL neurobiology , *NEURODEGENERATION , *LABORATORY mice , *ALZHEIMER'S disease , *SHORT-term memory , *NEUROPATHY , *MILD cognitive impairment - Abstract
Abstract: Environmental enrichment has been used in a variety of transgenic mouse models of Alzheimer''s disease (AD), however, with conflicting results. Here we studied the influence of environmental enrichment in a severely affected AD mouse model, showing a multiplicity of pathological alterations including hippocampal neuron loss. APP/PS1KI and wild type (WT) control mice were housed under standard conditions or in enriched cages equipped with various objects and running wheels. Amyloid plaque load, motor and working memory performance, axonopathy, as well as CA1 neuron number and hippocampal neurogenesis were assessed. Although a partial improvement in motor performance was observed, 4 months of enriched housing showed no beneficial effects in terms of working memory, Aβ plaque pathology, or neuron loss in APP/PS1KI mice. In addition, no changes in hippocampal neurogenesis and even an aggravation of the axonal phenotype were detected with a tendency toward a premature death. The APP/PS1KI model represents a model for mild to severe AD showing early behavioral deficits starting at 2 months of age with fast deterioration. Therefore our data might suggest that physical activity and enriched environment might be more beneficial in patients with mild cognitive impairment than in patients with incipient AD. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
33. Overexpression of Glutaminyl Cyclase, tthe Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice.
- Author
-
Jawhar, Sadim, Wirths, Oliver, Schilling, Stephan, Graubner, Sigrid, Demuth, Hans-Ulrich, and Bayer, Thomas A.
- Subjects
- *
ALZHEIMER'S disease , *GENE expression , *PHENOTYPES , *TRANSGENIC mice , *ENZYMES , *NEURONS , *PEPTIDES , *DISEASES - Abstract
Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
34. Concomitant detection of β-amyloid peptides with N-terminal truncation and different C-terminal endings in cortical plaques from cases with Alzheimer's disease, senile monkeys and triple transgenic mice
- Author
-
Härtig, Wolfgang, Goldhammer, Simone, Bauer, Ute, Wegner, Florian, Wirths, Oliver, Bayer, Thomas A., and Grosche, Jens
- Subjects
- *
AMYLOID beta-protein , *ALZHEIMER'S disease research , *RHESUS monkeys , *TRANSGENIC mice , *AMYLOIDOSIS , *DISEASE progression , *IMMUNOFLUORESCENCE , *ANIMAL disease models - Abstract
Abstract: The disturbed metabolism of β-amyloid peptides generated from amyloid precursor protein is widely considered as a main factor during the pathogenesis of Alzheimer''s disease. A neuropathological hallmark in the brains from cases with Alzheimer''s disease are senile plaques mainly composed of hardly soluble β-amyloid peptides comprising up to 43 amino acids. Age-dependent cortical β-amyloidosis was also shown in several transgenic mice and old individuals from various mammalian species, e.g., non-human primates. β-Amyloid1–42 is believed to be the main component in the core of senile plaques, whereas less hydrophobic β-amyloid1–40 predominantly occurs in the outer rim of plaques. Amino-terminally truncated pyroglutamyl-β-amyloidpE3–x was recently found to be a β-amyloid species of high relevance to the progression of the disease. While a few biochemical studies provided data on the co-occurrence of several β-amyloid forms, their concomitant histochemical detection is still lacking. Here, we present a novel triple immunofluorescence labelling of amino- and differently carboxy-terminally truncated β-amyloid peptides in cortical plaques from a case with Alzheimer''s disease, senile macaques and baboons, and triple transgenic mice with age-dependent β-amyloidosis and tau hyperphosphorylation. Additionally, β-amyloidpE3–x and total β-amyloid were concomitantly detected with β-amyloid peptides ending with amino acid 40 or 42, respectively. Simultaneous staining of several β-amyloid species reveals for instance vascular amyloid containing β-amyloidpE3–x in Alzheimer''s disease and monkeys, and may contribute to the further elucidation of β-amyloidosis in neurodegenerative disorders and animal models. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
35. Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease
- Author
-
Wirths, Oliver, Breyhan, Henning, Marcello, Andrea, Cotel, Marie-Caroline, Brück, Wolfgang, and Bayer, Thomas A.
- Subjects
- *
NEURODEGENERATION , *BRAIN , *SPINAL cord , *INFLAMMATION , *ALZHEIMER'S disease , *OXIDATIVE stress , *AMYLOID , *ANIMAL disease models , *LABORATORY mice - Abstract
Abstract: Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer''s disease (AD). In the present study, we performed a systematic expression analysis of various inflammatory and oxidative stress markers in pre-symptomatic and diseased APP/PS1KI mice. This mouse model has been previously shown to harbor severe pathological alterations, including behavioral deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. While the expression levels of most markers remained unchanged in 2-month-old APP/PS1KI mice, at the age of 6 months different astro- and microglia markers including GFAP, Cathepsin D, members of the Toll-like receptor (Tlr) family, TGFβ-1 and osteopontin were up-regulated. In addition, oxidative stress markers, including the metallothioneins, were also significantly elevated at that time point. As expected, both brain and spinal cord were affected, the latter showing early activation of GFAP-positive astrocytes and Iba1-positive microglia in white matter fiber tracts, which might contribute to the previously reported axonal defects in this mouse model. These data add further evidence to the assumption that inflammatory processes are tightly associated with axonal degeneration and neuron loss, as is evident in the APP/PS1KI mouse model. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
36. Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease
- Author
-
Wirths, Oliver, Breyhan, Henning, Schäfer, Stephanie, Roth, Christian, and Bayer, Thomas A.
- Subjects
- *
ALZHEIMER'S disease , *SENILE dementia , *PRESENILE dementia , *CENTRAL nervous system - Abstract
Abstract: The APP/PS1ki mouse model for Alzheimer''s disease (AD) exhibits robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss starting at 6 months of age. It expresses human mutant APP751 with the Swedish and London mutations together with two FAD-linked knocked-in mutations (PS1 M233T and PS1 L235P) in the murine PS1 gene. The present report covers a phenotypical analysis of this model using either behavioral tests for working memory and motor performance, as well as an analysis of weight development and body shape. At the age of 6 months, a dramatic, age-dependent change in all of these properties and characteristics was observed, accompanied by a significantly reduced ability to perform working memory and motor tasks. The APP/PS1ki mice were smaller and showed development of a thoracolumbar kyphosis, together with an incremental loss of body weight. While 2-month-old APP/PS1ki mice were inconspicuous in all of these tasks and properties, there is a massive age-related impairment in all tested behavioral paradigms. We have previously reported robust axonal degeneration in brain and spinal cord, as well as abundant hippocampal CA1 neuron loss starting at 6 months of age in the APP/PS1ki mouse model, which coincides with the onset of motor and memory deficits described in the present report. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
37. Age-dependent axonal degeneration in an Alzheimer mouse model
- Author
-
Wirths, Oliver, Weis, Joachim, Kayed, Rakez, Saido, Takaomi C., and Bayer, Thomas A.
- Subjects
- *
AXONAL transport , *NEURODEGENERATION , *NEUROMUSCULAR diseases , *SPINAL cord - Abstract
Abstract: Some neurodegenerative diseases including Alzheimer''s disease (AD) and amyotrophic lateral sclerosis (ALS) exhibit prominent defects in axonal transport. These defects can manifest as axonal swellings or spheroids, which correspond to axonal enlargements and aberrant accumulation of axonal cargoes, cytoskeletal proteins and lipids. Recently, a controversial scientific debate focussed on the issue whether Aβ serves as a trigger for aberrant axonal transport in the pathophysiology of AD. Prominent axonopathy has been shown to be induced by overexpression of proteins involved in several neurodegenerative diseases. Neurofilament, apolipoprotein E, Niemann-Pick protein and Tau transgenic mice with axonal trafficking deficits have been reported. Furthermore, motor deficits are frequently observed in patients with AD, which has been attributed to the typical tauopathy in post-mortem brain tissue. In the present report, we analyzed axonal neuropathology in the brain and spinal cord of a transgenic mouse model with abundant intraneuronal Aβ42 production and provide compelling evidence for axonal degeneration. The APP/PS1ki mice showed characteristic axonal swellings, spheroids, axonal demyelination and ovoids, which are myelin remnants of degenerated nerve fibers in an age-dependent manner. Abundant accumulation of intraneuronal N-modified Aβ, Thioflavin S-positive material and ubiquitin was found within the somatodendritic compartment of neurons. We conclude that the intraneuronal accumulation of Aβ-amyloid peptides is followed by axonal degeneration, and thus might be a causative factor for the axonal changes seen in AD. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
38. Decreased plasma cholesterol levels during aging in transgenic mouse models of Alzheimer's disease
- Author
-
Wirths, Oliver, Thelen, Karin, Breyhan, Henning, Luzón-Toro, Berta, Hoffmann, Karl-Heinz, Falkai, Peter, Lütjohann, Dieter, and Bayer, Thomas A.
- Subjects
- *
TRANSGENIC animals , *ALZHEIMER'S disease , *RODENTS , *AGING - Abstract
Abstract: A large number of studies deals with the association of cholesterol and Aβ levels, however, the results are so far controversial. Whereas some studies report on increased cholesterol levels, other authors refer to an association of decreased peripheral cholesterol and the incidence of Alzheimer''s disease. It is also questionable whether plasma cholesterol levels could be used as a predictive biomarker for the incidence of Alzheimer''s disease. In the present report, we studied the relationship between these two parameters during aging in different transgenic mouse models of Alzheimer''s disease, expressing both mutant human amyloid precursor protein and mutant human presenilin-1. Measurements of plasma cholesterol levels revealed a significant reduction in aged APP/PS1 and APP/PS1ki mice, whereas plasma levels in young and aged control mice remained almost unchanged. Furthermore, statistical analysis revealed a significant negative correlation between plasma cholesterol and brain Aβ42 levels during aging in the mice expressing both APP and PS1. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
39. No improvement after chronic ibuprofen treatment in the 5XFAD mouse model of Alzheimer's disease
- Author
-
Hillmann, Antje, Hahn, Stefanie, Schilling, Stephan, Hoffmann, Torsten, Demuth, Hans-Ulrich, Bulic, Bruno, Schneider-Axmann, Thomas, Bayer, Thomas A., Weggen, Sascha, and Wirths, Oliver
- Subjects
- *
IBUPROFEN , *ALZHEIMER'S disease , *ANTI-inflammatory agents , *CYCLOOXYGENASES , *SECRETASES , *LABORATORY mice - Abstract
Abstract: Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that has been reported to reduce the risk of developing Alzheimer''s disease (AD). Its preventive effects in AD are likely pleiotropic as ibuprofen displays both anti-inflammatory activity by inhibition of cyclooxygenases and anti-amyloidogenic activity by modulation of γ-secretase. In order to study the anti-inflammatory properties of ibuprofen independent of its anti-amyloidogenic activity, we performed a long-term treatment study with ibuprofen in 5XFAD mice expressing a presenilin-1 mutation that renders this AD model resistant to γ-secretase modulation. As expected, ibuprofen treatment for 3 months resulted in a reduction of the inflammatory reaction in the 5XFAD mouse model. Importantly, an unchanged amyloid beta (Aβ) plaque load, an increase in soluble Aβ42 levels, and an aggravation of some behavioral parameters were noted, raising the question whether suppression of inflammation by nonsteroidal anti-inflammatory drug is beneficial in AD. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
40. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease
- Author
-
Jawhar, Sadim, Trawicka, Anna, Jenneckens, Carolin, Bayer, Thomas A., and Wirths, Oliver
- Subjects
- *
ANXIETY , *NEURODEGENERATION , *ALZHEIMER'S disease , *LABORATORY mice , *SHORT-term memory , *NEUROLOGICAL disorders , *SPINAL cord - Abstract
Abstract: In the present report, we extend previous findings in the 5XFAD mouse model and demonstrate that these mice develop an age-dependent motor phenotype in addition to working memory deficits and reduced anxiety levels as demonstrated in an elevated plus maze task. Employing a variety of N- and C-terminal specific Aβ antibodies, abundant intraneuronal and plaque-associated pathology, including accumulation of pyroglutamate Aβ, was observed as early as the age of 3 months. Using unbiased stereology, we demonstrate that the 5XFAD mice develop a significant selective neuron loss in layer 5 of the cortex, leaving the overall neuron number of the total frontal cortex and hippocampus unaffected. This observation coincides with the accumulation of intraneuronal Aβ peptides only in cortical Layer 5, but not in CA1, despite comparable APP expression levels. The motor phenotype correlates with abundant spinal cord pathology, as demonstrated by abundant intraneuronal Aβ accumulation and extracellular plaque deposition. In addition, comparable to the APP/PS1KI mouse model, 5XFAD mice develop an age-dependent axonopathy likely contributing to the behavioral deficits. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
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