Alzheimer's disease amyloid propagation by a template-dependent dock- lock mechanism

William P. Esler, Evelyn R. Stimson, Joan M. Jennings, Harry V. Vinters, Joseph R. Ghilardi, Jonathan P. Lee, Patrick W. Mantyh, John E. Maggio

Research output: Contribution to journalArticlepeer-review

302 Scopus citations

Abstract

Amyloid plaques composed of the peptide Aβ are an integral part of Alzheimer's disease (AD) pathogenesis. We have modeled the process of amyloid plaque growth by monitoring the deposition of soluble Aβ onto amyloid in AD brain tissue or synthetic amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, 'dock', Aβ addition to the amyloid template is fully reversible (dissociation t(1/2) ≃ 10 min), while in the second phase, 'lock', the deposited peptide becomes irreversibly associated (dissociation t(1/2) >> 1000 min) with the template in a time- dependent manner. The most recently deposited peptide dissociates first while Aβ previously deposited becomes irreversibly 'locked' onto the template. Thus, the transition from monomer to neurotoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two Aβ peptides bearing primary sequence alterations implicated in heritable Aβ amyloidoses displayed faster lock- phase kinetics than wild-type Aβ. Inhibiting the initial weak docking interaction between depositing Aβ and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of Aβ((solution)) to Aβ((amyloid)) and thus prevent stable amyloid accumulation. While thermodynamics suggest that inhibiting amyloid assembly would be difficult, the present study illustrates that the protein misfolding diseases are kinetically vulnerable to intervention.

Original languageEnglish (US)
Pages (from-to)6288-6295
Number of pages8
JournalBiochemistry
Volume39
Issue number21
DOIs
StatePublished - May 30 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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