A reduction in the number of cholinergic neurons in the basal forebrain has also been observed at 6 months ( Devi and Ohno, 2010). In the areas with the most severe amyloidosis-the subiculum and cortical layer V-neuron loss begins at about 6 months of age ( Oakley et al., 2006 Eimer and Vassar, 2013). Neuron loss has been observed in multiple brain regions in this model. In an ultrastructural study of synapses in the hippocampi of 12-month mice, an almost 50 percent loss of axospinous synapses was found in stratum lacunosum-moleculare, while synapse numbers in the stratum radiatum of 5xFAD mice did not differ from non-transgenic controls ( Neuman et. Little information is available about the spatiotemporal pattern or details of synapse loss. Synaptic degeneration, assessed as whole-brain levels of the presynaptic marker synaptophysin, begins by four months of age levels of syntaxin, another presynaptic marker, and PSD-95, a postsynaptic marker, decline by 9 months ( Oakley et al., 2006). Females exhibit more aggressive plaque pathology: plaque numbers in the hippocampus and cortex are higher in females than in males, and continue to increase until at least 14 months of age, while numbers in males plateau at 10 months ( Bhattacharya et al., 2014).Īstrogliosis and microgliosis begin around two months, developing in parallel with plaque deposition ( Oakley et al., 2006). Amyloid pathology has also been observed in the spinal cord, appearing at 11 weeks in cervical and lumbar regions and extending along the length of the cord by 19 weeks ( Chu et al., 2017). Plaques are found throughout the hippocampus and cortex by six months in older mice, plaques are present in the thalamus, brainstem, and olfactory bulb, but are absent from the cerebellum ( Oakley et al., 2006).
Staining with thioflavin S suggests that intracellular Aβ42 may form β-pleated sheet aggregates ( Oakley et al., 2006).Įxtracellular amyloid deposition begins around 2 months, first in the subiculum and layer V of the cortex, and increasing rapidly with age. Intracellular immunoreactivity for Aβ was observed to co-localize with that for cathepsin-D, a maker of lysosomes and other acidic organelles ( Youmans et al., 2012). These mice accumulate high levels of intraneuronal Aβ42, beginning around 1.5 months of age ( Oakley et al., 2006). The 5xFAD model rapidly develops severe amyloid pathology. An age-dependent increase in BACE1 has also been reported ( Devi and Ohno, 2010 Maarouf et al., 2013). Aβ40 levels also increase with age, but rise more slowly and are substantially lower than for Aβ42, with the Aβ42:Aβ40 ratio reaching as high as 25 in young animals ( Oakley et al., 2006). Soluble Aβ42 is detectable by 1.5 months and its levels increase steeply with age. Females express somewhat more APP than males, probably due to an estrogen response element in the Thy1 promoter used to drive transgene expression ( Sadleir et al., 2015 Sadleir et al., 2018), and generate higher levels of Aβ ( Oakley et al., 2006 Maarouf et al., 2013). Levels of human APP in whole brain have been reported as between half ( Sadleir et al., 2018) and three times ( Ohno et al., 2006) that of endogenous mouse APP, and levels of transgenic PS1 as half those of the endogenous protein ( Sadleir et al., 2018). The descriptions on this page refer to mice hemizygous for the APP and PSEN1 transgenes. Mice display a range of cognitive and motor deficits. Neuron loss occurs in multiple brain regions, beginning at about 6 months in the areas with the most pronounced amyloidosis. Amyloid pathology is more severe in females than in males. Amyloid plaques, accompanied by gliosis, are seen in mice as young as two months of age. These widely used mice recapitulate many AD-related phenotypes and have a relatively early and aggressive presentation. Tg6799 mice are also available on a congenic C57BL6 background, described elsewhere.
The Tg6799 line, which expresses the highest levels of mutant APP, is the most studied of the three, and is described here on the original hybrid B6SJL background.
Three lines were generated originally: Tg6799, Tg7031, and Tg7092.
SummaryĥxFAD mice express human APP and PSEN1 transgenes with a total of five AD-linked mutations: the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations in APP, and the M146L and L286V mutations in PSEN1. Research with this model is available from QPS Austria. Species: Mouse Genes: APP, PSEN1 Mutations: APP KM670/671NL (Swedish), APP I716V, APP V717I, PSEN1 M146L (A>C), PSEN1 L286V Modification: APP: Transgenic PSEN1: Transgenic Disease Relevance: Alzheimer's Disease Strain Name: B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax Genetic Background: C57BL/6 x SJL Availability: The Jackson Lab available through the JAX MMRRC Stock# 034840 Live.
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