Published online 3 October 2005. doi:10.1083/jcb1711iti3
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 1, 9-9
New route to Aß
On page 87, Yu et al. reveal that autophagic vesicles (AVs) are a breeding ground for the toxic ß-amyloid peptide (Aß). Prevention of abnormal AV accumulation might thus ward off Alzheimer's disease (AD).
Aß had previously been localized to nebulous endocytic compartments. Based on evidence that AVs in liver contain the Aß precursor, Yu et al. wondered whether autophagocytosis also creates Aß. They found that isolated neuronal AVs contained Aß and were highly enriched for the enzymes that create it. AVs were a major source of intracellular Aß, which is increasingly thought to be more toxic than the secreted form.
Healthy brain tissue rarely contained AVs and thus accumulated little Aß. 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 Aß, but this fusion apparently failed in the diseased neurons.
High levels of Aß, as in AD neurons, were seen in cells in which the authors used nutrient starvation to induce autophagy. Suppressing autophagy, in contrast, decreased Aß production. If Aß oligomers create holes in membranes, as has been proposed, caustic or partially degraded AV proteins might escape into the cytoplasm. Along with Aß, these troublemakers might be dealt with by therapeutic treatments that promote their digestion, such as AV acidification. 
Nicole LeBrasseur
lebrasn{at}rockefeller.edu
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