Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta 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 (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.
McLaurin
J
J
Centre for Research in Neurodegenerative Diseases, University of Toronto, Canada.
Franklin
T
T
Chakrabartty
A
A
Fraser
P E
PE
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002417:Cattle; D007294:Inositol / Q000737:chemistry / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D013997:Time Factors
D016229:Amyloid beta-Peptides; D007295:Inositol Phosphates; D010446:Peptide Fragments; D010716:Phosphatidylinositols; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C002647:inositol 1-phosphate; C044259:inositol 1,4-bis(phosphate); D007294:Inositol; D015544:Inositol 1,4,5-Trisphosphate