Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of -amyloid 42 (A 42 ) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce A 42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral A 42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase A 42 production. 5XFAD mice generate A 42 almost exclusively and rapidly accumulate massive cerebral A 42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal A 42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal A. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal A 42 -induced neurodegeneration and amyloid plaque formation.
Eight Earth System Models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) are evaluated, focusing on both the net carbon dioxide flux and its components and their relation with climatic variables (temperature, precipitation, and soil moisture) in the historical (1850–2005) and representative concentration pathway 4.5 (RCP4.5; 2006–2100) simulations. While model results differ, their median globally averaged production and respiration terms from 1976 to 2005 agree reasonably with available observation-based products. Disturbances such as land use change are roughly represented but crucial in determining whether the land is a carbon source or sink over many regions in both simulations. While carbon fluxes vary with latitude and between the two simulations, the ratio of net to gross primary production, representing the ecosystem carbon use efficiency, is less dependent on latitude and does not differ significantly in the historical and RCP4.5 simulations. The linear trend of increased land carbon fluxes (except net ecosystem production) is accelerated in the twenty-first century. The cumulative net ecosystem production by 2100 is positive (i.e., carbon sink) in all models and the tropical and boreal latitudes become major carbon sinks in most models. The temporal correlations between annual-mean carbon cycle and climate variables vary substantially (including the change of sign) among the eight models in both the historical and twenty-first-century simulations. The ranges of correlations of carbon cycle variables with precipitation and soil moisture are also quite different, reflecting the important impact of the model treatment of the hydrological cycle on the carbon cycle.
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