Early and Late Cytotoxic Effects of External Application of the Alzheimer's Aβ Result from the Initial Formation and Function of Aβ Ion Channels

• Published in: Biochemistry (Easton) 2006-05, Vol.45 (18), p.5907-5915
• Main Authors: Simakova, Olga, Arispe, Nelson J
• Format: Article
• Language: English
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi060148g

Extracellular application of the Alzheimer's beta-amyloid (Aβ) peptide evokes a series of cellular responses that leads to the death of cells by apoptosis. Some responses to freshly prepared Aβ occur immediately, including changes in intracellular calcium concentration and changes in membrane permeability and phosphatidylserine asymmetry. We show here that the cytotoxic action of externally applied Aβ, such as caspase activation and apoptotic loss of cell viability, occurs and persists even several days after Aβ is removed from the medium. We find that the mechanism for this persistent cytotoxic action of extracellular Aβ is based on the sustained activity of active Aβ ion channels that remain incorporated in the cell membrane. To confirm this assessment, we blocked the late cytotoxic action of Aβ with the classically known Aβ channel blockers zinc and tromethamine. To further validate this conclusion, we developed a specific peptide segment from the sequence forming the mouth of the Aβ channel to block Aβ Ca2+ channels acutely and to block late Aβ effects on caspase activation and apoptosis. This is the first report of a specific Aβ channel blocker compound, NA4, which efficaciously and potently blocks the most known cellular responses to Aβ.