Published online 28 January 2002. doi:10.1083/jcb1563iti1
© The Rockefeller University Press,
0021-9525/2002/2/411 $5.00
The Journal of Cell Biology, Volume 156, Number 3, February 4, 2002 411-411
With Aß, the danger lies within
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Intracellular injection of Aß1–42 induces neuronal cell death and TUNEL staining (green).
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The most obvious symptom is not always the most relevant. In Alzheimer's disease (AD), for example, post-mortem brain analyses show large extracellular amyloid plaques of fibrillar Aß protein. But the plaques arise late, whereas an intracellular version of the toxic protein fragment (Aß1–42, a fragment of the amyloid precursor protein) is seen earlier, coincident with the first cognitive defects. Now Zhang et al. (page 519) show that minute amounts of this intracellular Aß1–42 are toxic to primary neurons, even when injected directly into the cytoplasm.The final concentration of injected Aß1–42 is 1–100 pM, for a total of somewhere between 1,500 and 150,000 molecules per neuron. In contrast, the same neurons are not significantly affected by up to 10 µM extracellular Aß1–42, nor by intracellular Aß1–40, perhaps because the Aß1–40 cannot multimerize. Death requires transcription and translation, and the activities of p53, Bax, and caspase 6, probably in that order. The pathway from Aß1–42 to p53 remains a mystery. Zhang et al. are now looking at kinases that are known to regulate p53 activity.
What goes wrong first in AD is also not clear. If Aß1–42 exerts its activity in the cytoplasm it must first escape from the secretory pathway. Zhang et al. suggest this may happen by either reverse translocation from the ER or leakage from endosomes. As the details of these pathways are fleshed out, both the trafficking and apoptotic pathways may become excellent targets for AD drugs. 
William A. Wells
wellsw{at}rockefeller.edu
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