Early and Late Cytotoxic Effects of External Application of the Alzheimer's A Result from the Initial Formation and F
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  • 作者:Olga Simakova and Nelson J. Arispe
  • 刊名:Biochemistry
  • 出版年:2006
  • 出版时间:May 9, 2006
  • 年:2006
  • 卷:45
  • 期:18
  • 页码:5907 - 5915
  • 全文大小:576K
  • 年卷期:v.45,no.18(May 9, 2006)
  • ISSN:1520-4995
文摘
Extracellular application of the Alzheimer's beta-amyloid (A) peptide evokes a series ofcellular responses that leads to the death of cells by apoptosis. Some responses to freshly prepared Aoccur immediately, including changes in intracellular calcium concentration and changes in membranepermeability and phosphatidylserine asymmetry. We show here that the cytotoxic action of externallyapplied A, such as caspase activation and apoptotic loss of cell viability, occurs and persists even severaldays after A is removed from the medium. We find that the mechanism for this persistent cytotoxicaction of extracellular A is based on the sustained activity of active A ion channels that remainincorporated in the cell membrane. To confirm this assessment, we blocked the late cytotoxic action ofA with the classically known A channel blockers zinc and tromethamine. To further validate thisconclusion, we developed a specific peptide segment from the sequence forming the mouth of the Achannel to block A Ca2+ channels acutely and to block late A effects on caspase activation and apoptosis.This is the first report of a specific A channel blocker compound, NA4, which efficaciously and potentlyblocks the most known cellular responses to A.

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