Piracetam Inhibits The Lipid-Destabilising Effect Of The Amyloid Peptide A Beta C-Terminal Fragment

Amyloid peptide (Abeta) is a 40/42-residue proteolytic fragment of a precursor
protein (APP), implicated in the pathogenesis of Alzheimer's disease. The
hypothesis that interactions between Abeta aggregates and neuronal membranes play
an important role in toxicity has gained some acceptance. Previously, we showed
that the C-terminal domain (e.g. amino acids 29-42) of Abeta induces membrane
permeabilisation and fusion, an effect which is related to the appearance of
non-bilayer structures. Conformational studies showed that this peptide has
properties similar to those of the fusion peptide of viral proteins i.e. a tilted
penetration into membranes. Since piracetam interacts with lipids and has
beneficial effects on several symptoms of Alzheimer's disease, we investigated in
model membranes the ability of piracetam to hinder the destabilising effect of
the Abeta 29-42 peptide. Using fluorescence studies and 31P and 2H NMR
spectroscopy, we have shown that piracetam was able to significantly decrease the
fusogenic and destabilising effect of Abeta 29-42, in a concentration-dependent
manner. While the peptide induced lipid disorganisation and subsequent negative
curvature at the membrane-water interface, the conformational analysis showed
that piracetam, when preincubated with lipids, coats the phospholipid headgroups.
Calculations suggest that this prevents appearance of the peptide-induced
curvature. In addition, insertion of molecules with an inverted cone shape, like
piracetam, into the outer membrane leaflet should make the formation of such
structures energetically less favourable and therefore decrease the likelihood of
membrane fusion.