Neuronal membrane conductance activated by amyloid β peptide: importance of peptide conformation

Abstract

Whole-cell voltage-clamp recording and circular dichroism (CD) spectroscopy were used to assess the importance of amyloid β peptide (A β) conformation for eliciting homeostatically disruptive membrane conductances in embryonic rat hippocampal neurons. A β that assumed a random coil conformation when freshly dissolved in water did not alter cell resting (‘leak’) membrane conductances. In contrast, after several days incubation (‘aging’), the same peptide samples became capable of activating a large, rapid onset and potentially toxic increase in leak membrane conductance that coincided temporally with a transition in peptide conformation from random coil to β-sheet. Interestingly, this membrane activity was not mimicked with chemically equivalent A βs that immediately adopted a β-sheet conformation in water (‘pre-aged’). These findings suggest that, under conditions that allow for a gradual transition of random coil A β to β-sheet structures, peptide conformation may be an important determinant of the toxic consequences of A β-mediated membrane conductances.