Extracellular application of the Alzheimer's beta-amyloid (A
![](/images/gifchars/beta2.gif)
) peptide evokes a series ofcellular responses that leads to the death of cells by apoptosis. Some responses to freshly prepared A
![](/images/gifchars/beta2.gif)
occur immediately, including changes in intracellular calcium concentration
and changes in membranepermeability
and phosphatidylserine asymmetry. We show here that the cytotoxic action of externallyapplied A
![](/images/gifchars/beta2.gif)
, such as caspase activation
and apoptotic loss of cell viability, occurs
and persists even severaldays after A
![](/images/gifchars/beta2.gif)
is removed from the medium. We find that the mechanism for this persistent cytotoxicaction of extracellular A
![](/images/gifchars/beta2.gif)
is based on the sustained activity of active A
![](/images/gifchars/beta2.gif)
ion channels that remainincorporated in the cell membrane. To confirm this assessment, we blocked the late cytotoxic action ofA
![](/images/gifchars/beta2.gif)
with the classically known A
![](/images/gifchars/beta2.gif)
channel blockers zinc
and tromethamine. To further validate thisconclusion, we developed a specific peptide segment from the sequence forming the mouth of the A
![](/images/gifchars/beta2.gif)
channel to block A
![](/images/gifchars/beta2.gif)
Ca
2+ channels acutely
and to block late A
![](/images/gifchars/beta2.gif)
effects on caspase activation
and apoptosis.This is the first report of a specific A
![](/images/gifchars/beta2.gif)
channel blocker compound, NA4, which efficaciously
and potentlyblocks the most known cellular responses to A
![](/images/gifchars/beta2.gif)
.