The monomers, oligomers, and fibrils of amyloid-β inhibit the activity of mitoBKCa channels by a membrane-mediated mechanism

A causative agent of Alzheimer's disease (AD) is a short amphipathic peptide called amyloid beta (A beta). A beta monomers undergo structural changes leading to their oligomerization or fibrillization. The monomers as well as all aggregated forms of A beta, i.e., oligomers, and fibrils, can bind to biological membranes, thereby modulating membrane mechanical properties. It is also known that some isoforms of the large-conductance calcium-activated potassium (BKCa) channel, including the mitochondrial BKCa (mitoBK(Ca)) channel, respond to mechanical changes in the membrane. Here, using the patch-clamp technique, we investigated the impact of full-length A beta (A beta(1-42)) and its fragment, A beta(25-35), on the activity of mitoBK(Ca) channels. We found that all forms of A beta inhibited the activity of the mitoBK(Ca) channel in a concentration-dependent manner. Since monomers, oligomers, and fibrils of A beta exhibit different molecular characteristics and structures, we hypothesized that the inhibition was not due to direct peptide-protein interactions but rather to membrane-binding of the A beta peptides. Our findings supported this hypothesis by showing that A beta peptides block mitoBK(Ca) channels irrespective of the side of the membrane to which they are applied. In addition, we found that the enantiomeric peptide, D-A beta(1-42), demonstrated similar inhibitory activity towards mitoBK(Ca) channels. As a result, we proposed a general model in which all A beta forms i.e., monomers, oligomers, and amyloid fibrils, contribute to the progression of AD by exerting a modulatory effect on mechanosensitive membrane components.