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  • Nature Publishing Group (CrossRef)  (33)
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  • 1
    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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  • 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: Nature Chemistry, 2017
    Description: The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.
    Keywords: Roentgen-Beam ; Protein-Synthesis ; Computer-Modelling ; Cytotoxic-Agents ; Halogens ; Ligands ; Chlorides ; Natural-Products ; Cell-Lines ; Secondary-Metabolites ; Ribosome ; 2-Amino-1h-Purin-6:9h:One ; X-Strahl ; Proteinsynthese ; Computer-Modell ; Zytotoxin ; Halogene ; Ligand ; Chlorid ; Nachwachsender Rohstoff ; Zelllinie ; Sekundärstoffwechselprodukt ; Ribosom ; Guanin ; Chemistry;
    ISSN: 1755-4330
    E-ISSN: 1755-4349
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  • 5
    Language: English
    In: Nature medicine, July 2015, Vol.21(7), pp.802-7
    Description: Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.
    Keywords: Amyloid Beta-Peptides -- Metabolism ; Plaque, Amyloid -- Metabolism ; Alpha-Synuclein -- Metabolism
    ISSN: 10788956
    E-ISSN: 1546-170X
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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: Obesity (Silver Spring, Md.), June 2012, Vol.20(6), pp.1279-87
    Description: We examined the association between sleep duration and BMI in young adults, and, specifically, in possible gender differences. The population-based sample included 955 young men and 1051 young women (mean age = 25.3 years, s.d. = 1.7) who participated in Project EAT-III (Eating and Activity in Teens and Young Adults)-III. In 2008-2009, study participants completed a survey, on which they reported their weight, height, and typical bed and awakening times. Gender-specific regression models estimated cross-sectional associations between sleep duration and weight status, adjusting for age, race, SES, family structure, depressive symptoms, physical activity, and sedentary and dietary behaviors. In multivariable-adjusted linear regression models, an hour increase in sleep was associated with a -0.38 (-0.70, -0.048) BMI in men. Men who slept 〈7 h had a 1.4 unit higher mean BMI (27.9; 95% confidence interval (CI): 26.9, 28.9) than men who slept 7-9 h/day (26.5; 95% CI: 26.1, 27.0). Prevalence estimates of overweight (BMI ≥ 25) and obesity (BMI ≥ 30) were also inversely associated with sleep duration among men. Sleep duration was not associated with BMI, overweight, or obesity in women. Among women, but not men, there was a statistically significant positive association between trouble falling or staying asleep and mean BMI. Sleep may be an important modifiable risk factor for obesity, particularly in young adult men.
    Keywords: Body Mass Index ; Sleep ; Obesity -- Etiology ; Sleep Initiation and Maintenance Disorders -- Complications
    ISSN: 10976256
    ISSN: 19307381
    E-ISSN: 1930-739X
    E-ISSN: 15461726
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  • 8
    Language: English
    In: Obesity (Silver Spring, Md.), June 2012, Vol.20(6), pp.1279-87
    Description: We examined the association between sleep duration and BMI in young adults, and, specifically, in possible gender differences. The population-based sample included 955 young men and 1051 young women (mean age = 25.3 years, s.d. = 1.7) who participated in Project EAT-III (Eating and Activity in Teens and Young Adults)-III. In 2008-2009, study participants completed a survey, on which they reported their weight, height, and typical bed and awakening times. Gender-specific regression models estimated cross-sectional associations between sleep duration and weight status, adjusting for age, race, SES, family structure, depressive symptoms, physical activity, and sedentary and dietary behaviors. In multivariable-adjusted linear regression models, an hour increase in sleep was associated with a -0.38 (-0.70, -0.048) BMI in men. Men who slept 〈7 h had a 1.4 unit higher mean BMI (27.9; 95% confidence interval (CI): 26.9, 28.9) than men who slept 7-9 h/day (26.5; 95% CI: 26.1, 27.0). Prevalence estimates of overweight (BMI ≥ 25) and obesity (BMI ≥ 30) were also inversely associated with sleep duration among men. Sleep duration was not associated with BMI, overweight, or obesity in women. Among women, but not men, there was a statistically significant positive association between trouble falling or staying asleep and mean BMI. Sleep may be an important modifiable risk factor for obesity, particularly in young adult men.
    Keywords: Body Mass Index ; Sleep ; Obesity -- Etiology ; Sleep Initiation and Maintenance Disorders -- Complications
    ISSN: 10976256
    ISSN: 19307381
    E-ISSN: 1930-739X
    E-ISSN: 15461726
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  • 9
    Language: English
    In: Kidney International, September 2013, Vol.84(3), pp.532-544
    Description: The role of parietal epithelial cells (PECs) in glomerular disease is unclear because they also express podocyte proteins under pathophysiological conditions. To help resolve this, we established a novel PEC isolation technique in rats and mice to investigate which regulatory mechanisms lead to podocyte protein expression in PECs. This pure pool of naive PECs was then compared with PECs in primary culture and immortalized PECs in permanent culture. The naive PECs expressed low levels of podocyte-specific mRNA. Accordingly, in crescentic glomerulonephritis, single PECs activated the podocin promoter In primary culture, PECs expressed a distinct morphology from podocytes but with high transcript and protein levels of PEC markers. In contrast to naive PECs, cultured PECs also expressed podocyte proteins, and this correlated with reduced proteolytic activity but not with increased transcript levels. Activation of autophagy or proteasomal degradation decreased the levels of podocyte proteins in PECs, whereas inhibition of proteasomal degradation led to the stabilization of podocyte proteins in PECs. Thus, naive PECs express podocyte transcripts physiologically and these podocyte proteins are stable under pathological conditions through decreased proteolysis.
    Keywords: Glomerular Parietal Epithelial Cell ; Podocyte ; Primary Culture ; Proteolysis ; Medicine
    ISSN: 0085-2538
    E-ISSN: 1523-1755
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  • 10
    In: Nature, 1999, Vol.397(6721), p.661
    Description: The final paragraph of the Letter by Perrett et al., on the effects of sexual dimorphism on facial attractiveness, remarks that "preferences would encourage a youthful, neotenous appearance in the species generally". But this conflicts with the semantics...
    Keywords: Aging ; Beauty ; Face ; Female ; Humans ; Male ; Sex Characteristics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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