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

• Published in: Journal of molecular biology Vol. 278; no. 1; pp. 183 - 194
• Main Authors: McLaurin, J, Franklin, T, Chakrabartty, A, Fraser, P.E
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 24.04.1998
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; amyloid; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - metabolism; Animals; Cattle; circular dichroism; electron microscopy; Inositol - chemistry; Inositol - metabolism; Inositol 1,4,5-Trisphosphate - metabolism; Inositol Phosphates - metabolism; Peptide Fragments - analysis; Peptide Fragments - metabolism; phosphatidylinositol; Phosphatidylinositols - metabolism; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Protein Conformation; Time Factors; PBS; amyloid; AD; Alzheimer’s disease; phosphatidylinositol; IP; electron microscopy; PI; IP2; circular dichroism; IP3; PIP2
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1006/jmbi.1998.1677

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-β peptide (Aβ) which is an internal proteolytic fragment of the integral membrane amyloid precursor protein. Aggregation of Aβ 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 Aβ interactions with membrane proteins and/or lipids. Using circular dichroism spectroscopy, tyrosine fluorescence spectroscopy and electron microscopy, we have examined the binding of Aβ peptides 1-40 (Aβ40) and 1–42 (Aβ42) to the glycolipid, phosphatidylinositol (PI), and different inositol headgroups. At pH 6.0 and in the presence of PI vesicles, both Aβ40 and Aβ42 adopted an amyloidogenic β-structure. In contrast, at neutral pH only Aβ42 folded into a β-structure in the presence of PI vesicles. To determine whether the induction of β-structure stemmed from interactions with the headgroup of PI, the effects of inositol derivatives on Aβ were also examined. At pH 7.0, myo-inositol was sufficient to induce β-structure in Aβ42 but had no effect on the conformation of Aβ40. Myo-inositol may promote β-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 β-structure in both peptides. The results from this study indicate that interaction of Aβ40 and Aβ42 with PI acts as a seed for fibril formation while myo-inositol stabilizes a soluble Aβ42 micelle.