Phosphatidylinositol and inositol involvement in Alzheimer amyloid-β fibril growth and arrest

A key pathological feature of Alzheimer's disease is the formation and accumulation of amyloid fibres. The major component is the 39 to 42 residue amyloid-beta peptide (A beta) which is an internal proteolytic fragment of the integral membrane amyloid precursor protein. Aggregation of A beta into insoluble amyloid fibres is a nucleation-dependent event that may be modulated by the presence of amyloid-associated molecules. Fibril formation is also associated with neurotoxicity which may be the result of specific A beta interactions with membrane proteins and/or lipids. Using circular dichroism spectroscopy, tyrosine fluorescence spectroscopy and electron microscopy, we have examined the binding of A beta peptides 1-40 (A beta 40) and 1-42 (A beta 42) to the glycolipid, phosphatidylinositol (PI), and different inositol headgroups. At pH 6.0 and in the presence of PI vesicles, both A beta 40 and A beta 42 adopted an amyloidogenic beta-structure. In contrast, at neutral pH only A beta 42 folded into a beta-structure in the presence of PI vesicles. To determine whether the induction of beta-structure stemmed from interactions with the headgroup of PI, the effects of inositol derivatives on A beta were also examined. At pH 7.0, myo-inositol was sufficient to induce beta-structure in A beta 42 but had no effect on the conformation of A beta 40. Myo-inositol may promote beta-structure as a result of its ability to be both a hydrogen-bond donor and acceptor. Mono-, di- and triphosphorylated forms of inositol had reduced ability to induce beta-structure in both peptides. The results from this study indicate that interaction of A beta 40 and A beta 42 with PI acts as a seed for fibril formation while myoinositol stabilizes a soluble A beta 42 micelle. (C) 1998 Academic Press Limited.