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A? had previously been localized to nebulous endocytic compartments. Based on evidence that AVs in liver contain the A? precursor, Yu et al. wondered whether autophagocytosis also creates A?. They found that isolated neuronal AVs contained A? and were highly enriched for the enzymes that create it. AVs were a major source of intracellular A?, which is increasingly thought to be more toxic than the secreted form.
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; [6 Z+ p" n9 LHealthy brain tissue rarely contained AVs and thus accumulated little A?. But the authors found that neurons of brains in the early stages of AD, before neurodegeneration was apparent, contained unusually high numbers of AVs. These compartments normally fuse with degradative lysosomes, which might get rid of any A?, but this fusion apparently failed in the diseased neurons.
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High levels of A?, as in AD neurons, were seen in cells in which the authors used nutrient starvation to induce autophagy. Suppressing autophagy, in contrast, decreased A? production. If A? oligomers create holes in membranes, as has been proposed, caustic or partially degraded AV proteins might escape into the cytoplasm. Along with A?, these troublemakers might be dealt with by therapeutic treatments that promote their digestion, such as AV acidification.(On page 87, Yu et al. reveal that autoph) |
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发表于 2009-3-6 08:44
发表于 2015-5-28 09:18
