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  • Disease Models, Animal  (26)
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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 March 2013, Vol.110(10), pp.3782-7
    Description: The study of genetic disease mechanisms relies mostly on targeted mouse mutants that are derived from engineered embryonic stem (ES) cells. Nevertheless, the establishment of mutant ES cells is laborious and time-consuming, restricting the study of the increasing number of human disease mutations discovered by high-throughput genomic analysis. Here, we present an advanced approach for the production of mouse disease models by microinjection of transcription activator-like effector nucleases (TALENs) and synthetic oligodeoxynucleotides into one-cell embryos. Within 2 d of embryo injection, we created and corrected chocolate missense mutations in the small GTPase RAB38; a regulator of intracellular vesicle trafficking and phenotypic model of Hermansky-Pudlak syndrome. Because ES cell cultures and targeting vectors are not required, this technology enables instant germline modifications, making heterozygous mutants available within 18 wk. The key features of direct mutagenesis by TALENs and oligodeoxynucleotides, minimal effort and high speed, catalyze the generation of future in vivo models for the study of human disease mechanisms and interventions.
    Keywords: Disease Models, Animal ; Germ-Line Mutation ; Genetic Diseases, Inborn -- Genetics ; Oligodeoxyribonucleotides -- Administration & Dosage
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2008, Vol.451(7179), p.720
    Description: Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    In: Nature Neuroscience, 2013, Vol.16(5), p.580
    Description: Astrocytes are thought to have important roles after brain injury, but their behavior has largely been inferred from postmortem analysis. To examine the mechanisms that recruit astrocytes to sites of injury, we used in vivo two-photon laser- scanning microscopy to follow the response of GFP-labeled astrocytes in the adult mouse cerebral cortex over several weeks after acute injury. Live imaging revealed a marked heterogeneity in the reaction of individual astrocytes, with one subset retaining their initial morphology, another directing their processes toward the lesion, and a distinct subset located at juxtavascular sites proliferating. Although no astrocytes actively migrated toward the injury site, selective proliferation of juxtavascular astrocytes was observed after the introduction of a lesion and was still the case, even though the extent was reduced, after astrocyte-specific deletion of the RhoGTPase Cdc42. Thus, astrocyte recruitment after injury relies solely on proliferation in a specific niche.
    Keywords: Astrocytes – Physiological Aspects ; Astrocytes – Health Aspects ; Scanning Microscopy – Methods ; Medical Lasers – Usage ; Cerebral Cortex – Physiological Aspects ; Cerebral Cortex – Health Aspects;
    ISSN: 1097-6256
    E-ISSN: 1546-1726
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  • 4
    In: Scientific Reports, 2015, Vol.5
    Description: The role of microglia in amyloid-β (Aβ) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Aβ plaque formation. We found that microglia ingested Aβ, thereby preventing plaque formation in OHSCs. Conversely, Aβ deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Aβ plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer's disease (FAD) mice. Since no loss of Aβ clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Aβ1-42 burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Aβ clearance capacity. These data may therefore explain why Aβ plaque formation has never been described in wild-type mice, and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Aβ plaque formation in a cell culture setting.
    Keywords: Alzheimer Disease -- Pathology ; Amyloid Beta-Peptides -- Metabolism ; Hippocampus -- Pathology ; Microglia -- Pathology ; Peptide Fragments -- Metabolism ; Plaque, Amyloid -- Pathology ; Prosencephalon -- Pathology;
    ISSN: 20452322
    E-ISSN: 20452322
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  • 5
    In: EMBO Journal, 17 January 2018, Vol.37(2), pp.167-182
    Description: Alzheimer's disease () is characterized by severe neuronal loss as well as the accumulation of amyloid‐β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion‐like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment. Prion‐like Aβ seeding impairs neurogenesis and enhances cell death leading to electrophysiological abnormalities and memory deficits. Environmental stimuli reverse this memory impairment and diminish Aβ seeding by activating phagocytic microglia. Seed‐induced Aβ deposits directly affect adult neurogenesis and induces cell death leading to impaired memory. Housing the mice in an environmental enrichment potently reverses neurogenic and memory deficits. Activated phagocytic microglia prevent Aβ seeding under enriched environmental condition. Environmental stimuli and voluntary exercise, known to ameliorate dementia rescue adult neurogenesis in transgenic mouse models by activating phagocytic microglia to reduce amyloid‐β seeding.
    Keywords: Adult Neurogenesis ; Alzheimer'S Disease ; Aβ Seeding ; Environmental Enrichment ; Microglia
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 6
    In: Nature Neuroscience, 2003, Vol.6(4), p.370
    Description: Amyloid precursor protein (APP) processing and the generation of beta -amyloid peptide (A beta ) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble A beta in the extracellular space is involved in the spread of A beta pathology, and that extracellular amyloid formation can lead to neurodegeneration.
    Keywords: Neural Transplantation and Regeneration;
    ISSN: 1097-6256
    E-ISSN: 1546-1726
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 11 January 2005, Vol.102(2), pp.479-84
    Description: Diffusion parameters of the extracellular space (ECS) are changed in many brain pathologies, disturbing synaptic as well as extrasynaptic "volume" transmission, which is based on the diffusion of neuroactive substances in the ECS. Amyloid deposition, neuronal loss, and disturbed synaptic transmission are considered to be the main causes of Alzheimer's disease dementia. We studied diffusion parameters in the cerebral cortex of transgenic APP23 mice, which develop a pathology similar to Alzheimer's disease. The real-time tetramethylammonium (TMA) method and diffusion-weighted MRI were used to measure the ECS volume fraction (alpha = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADC(TMA)), diffusing exclusively in the ECS and of water (ADC(W)). Measurements were performed in vivo in 6-, 8-, and 17- to 25-month-old hemizygous APP23 male and female mice and age-matched controls. In all 6- to 8-month-old APP23 mice, the mean ECS volume fraction, ADC(TMA), and ADC(W) were not significantly different from age-matched controls (alpha = 0.20 +/- 0.01; ADC(TMA), 580 +/- 16 microm(2).s(-1); ADC(W), 618 +/- 19 microm(2).s(-1)). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADC(W), significantly greater in females than in males, but no changes in ADC(TMA). ECS volume fraction increased (0.22 +/- 0.01) and ADC(TMA) decreased (560 +/- 7 microm(2).s(-1)) in aged APP23 mice. The impaired navigation observed in these animals in the Morris water maze correlated with their plaque load, which was twice as high in females (20%) as in males (10%) and may, together with changed ECS diffusion properties, account for the impaired extrasynaptic transmission and spatial cognition observed in old transgenic females.
    Keywords: Disease Models, Animal ; Alzheimer Disease -- Etiology ; Amyloid Beta-Protein Precursor -- Physiology ; Extracellular Space -- Metabolism
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 8
    Language: English
    In: Acta Neuropathologica, 2014, Vol.128(3), pp.333-345
    Description: Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer’s disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology—these benefits were abrogated by block of phagocytic function. In Alzheimer’s disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer’s disease.
    Keywords: Alzheimer’s disease ; Rett syndrome ; Mecp2 ; Phagocytosis ; Amyloid plaques ; Microglia ; In vivo two-photon microscopy ; Genome-wide association studies (GWAS)
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 9
    Language: English
    In: Methods, March 2011, Vol.53(3), pp.201-207
    Description: Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer’s disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer’s disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions.
    Keywords: Alzheimer ; Tau ; Plaque ; Multiphoton ; In Vivo Imaging ; Chemistry ; Anatomy & Physiology
    ISSN: 1046-2023
    E-ISSN: 1095-9130
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  • 10
    Language: English
    In: Acta Neuropathologica, 2013, Vol.126(2), pp.179-188
    Description: Amyloid-β (Aβ) plaque deposition plays a central role in the pathogenesis of Alzheimer’s disease (AD). Post-mortem analysis of plaque development in mouse models of AD revealed that plaques are initially small, but then increase in size and become more numerous with age. There is evidence that plaques can grow uniformly over time; however, a complementary hypothesis of plaque development is that small plaques cluster and grow together thereby forming larger plaques. To investigate the latter hypothesis, we studied plaque formation in APPPS1 mice using in vivo two-photon microscopy and immunohistochemical analysis. We used sequential pre- and post-mortem staining techniques to label plaques at different stages of development and to detect newly emerged plaques. Post-mortem analysis revealed that a subset (22 %) of newly formed plaques appeared very close (〈40 μm) to pre-existing plaques and that many close plaques (25 %) that were initially separate merged over time to form one single large plaque. Our results suggest that small plaques can cluster together, thus forming larger plaques as a complementary mechanism to simple uniform plaque growth from a single initial plaque. This study deepens our understanding of Aβ deposition and demonstrates that there are multiple mechanisms at play in plaque development.
    Keywords: Alzheimer’s disease ; Amyloid plaques ; APPPS1 transgenic mice ; Two-photon in vivo imaging
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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