Aβ42 and Aβ40 oligomers form transient and persistent pores with different time evolutions and toxicities

In Alzheimer’s disease (AD), formation of harmful self-gating pores formed by the insertion of amyloid beta oligomers (AβOs) into the plasma membrane have been shown to cause disruption of Ca 2+ homeostasis, leading to neuronal malfunctioning and degeneration. Among different isoforms, the most studied Aβ40 and Aβ42 are also believed to be the most toxic ones. Using single channel imaging, we show that both isoforms can form functionally distinct populations of Ca 2+ permeable pores, we named transient and persistent pores. The transient pores could be seen only for a few tens of milliseconds, while persistent pores can be observed for more than an hour. However, while the Ca 2+ -toxicity of pores formed by Aβ42Os tend to increase over time by displaying higher open probability and larger Ca 2+ permeability, pores formed by Aβ40Os show opposite time dependent behavior. We conclude that although both isoforms can form Ca 2+ permeable pores in the cell’s plasma membrane, pores due to Aβ42Os display worsening Ca 2+ toxicity over time.