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

J Mol Biol. 1998 Apr 24;278(1):183-94. doi: 10.1006/jmbi.1998.1677.

Abstract

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 (Abeta) which is an internal proteolytic fragment of the integral membrane amyloid precursor protein. Aggregation of Abeta 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 Abeta interactions with membrane proteins and/or lipids. Using circular dichroism spectroscopy, tyrosine fluorescence spectroscopy and electron microscopy, we have examined the binding of Abeta peptides 1-40 (Abeta40) and 1-42 (Abeta42) to the glycolipid, phosphatidylinositol (PI), and different inositol headgroups. At pH 6.0 and in the presence of PI vesicles, both Abeta40 and Abeta42 adopted an amyloidogenic beta-structure. In contrast, at neutral pH only Abeta42 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 Abeta were also examined. At pH 7.0, myo-inositol was sufficient to induce beta-structure in Abeta42 but had no effect on the conformation of Abeta40. 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 Abeta40 and Abeta42 with PI acts as a seed for fibril formation while myo-inositol stabilizes a soluble Abeta42 micelle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / analysis
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cattle
  • Inositol / chemistry
  • Inositol / metabolism*
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Inositol Phosphates / metabolism
  • Peptide Fragments / analysis
  • Peptide Fragments / metabolism
  • Phosphatidylinositols / metabolism*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Protein Conformation*
  • Time Factors

Substances

  • Amyloid beta-Peptides
  • Inositol Phosphates
  • Peptide Fragments
  • Phosphatidylinositols
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • inositol 1-phosphate
  • inositol 1,4-bis(phosphate)
  • Inositol
  • Inositol 1,4,5-Trisphosphate