Selective inhibition of Abeta fibril formation.

Abstract

We describe here an inhibitor of in vitro fibril formation, hexadecyl-N-methylpiperidinium (HMP) bromide, which is selective for the Alzheimer's disease peptide Abeta. At 10 microM, its IC50 for inhibiting Abeta aggregation at pH 5.8, HMP bromide does not inhibit fibril formation by other amyloidogenic polypeptides nor does it affect the folding stability of the beta-sheet-rich immunoglobulin VL domain REI. In addition, small structural modifications of HMP bromide reduce or eliminate its ability to inhibit pH 5.8 aggregation of Abeta. These indications of specificity, plus the ability of the molecule to inhibit A beta aggregation at concentrations almost an order of magnitude below its critical micelle concentration, suggest a mechanism of inhibition other than micellar solubilization of Abeta. HMP bromide is required in approximately a 1:1 stoichiometry for effective inhibition at pH 5.8. Although stoichiometric amounts of HMP bromide with respect to total Abeta inhibit Abeta fibril formation at pH 7.4, the molecule is incapable, at lower concentrations, of blocking the seeding of fibril formation by small amounts of added Abeta fibrils. The results suggest the existence of a binding surface on A beta capable of binding amphipathic molecules such as HMP bromide and which, when occupied, precludes assembly of A beta into amyloid fibrils. Molecules that bind to this site with high specificity may prove to be useful therapeutic agents for preventing or retarding the cerebral amyloid plaque formation implicated in Alzheimer's disease pathology.

• Authors: S J Wood, L MacKenzie, B Maleeff, M R Hurle, R Wetzel
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 271 Issue 8 Pg. 4086-92 (Feb 23 1996) ISSN: 0021-9258 [Print] United States
• PMID: 8626745 (Publication Type: Journal Article)

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Islet Amyloid Polypeptide
• Piperidines
• Prealbumin
• Congo Red
• hexadecyl-N-methylpiperidinium

Topics

• Alzheimer Disease (metabolism)
• Amyloid (drug effects, metabolism)
• Amyloid beta-Peptides (antagonists & inhibitors, chemistry, ultrastructure)
• Circular Dichroism
• Congo Red
• Humans
• Islet Amyloid Polypeptide
• Kinetics
• Microscopy, Electron
• Piperidines (pharmacology)
• Prealbumin (drug effects, metabolism)
• Protein Conformation
• Scattering, Radiation