Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations

Bertrand P. Tseng, William P. Esler, Clary B. Clish, Evelyn R. Stimson, Joseph R. Ghilardi, Harry V. Vinters, Patrick W Mantyh, Jonathan P. Lee, John E. Maggio

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Senile plaques composed of the peptide Aβ contribute to the pathogenesis of Alzheimer's disease (AD), and mechanisms underlying their formation and growth may be exploitable as therapeutic targets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusion chromatography (SEC), translational diffusion measured by NMR, and in vitro models of Aβ amyloid growth to identify the oligomerization state of Aβ that is competent to add onto an existing amyloid deposit. SEC of radiolabeled and unlabeled Aβ over a concentration range of 10-10-10-4 M demonstrated that the freshly dissolved peptide eluted as a single low molecular weight species, consistent with monomer or dimer. This low molecular weight Aβ species isolated by SEC was competent to deposit onto preexisting amyloid in preparations of AD cortex, with first-order kinetic dependence on soluble Aβ concentration, establishing that solution-phase oligomerization is not rate limiting. Translational diffusion measurements of the low molecular weight Aβ fraction demonstrate that the form of the peptide active in plaque deposition is a monomer. In deliberately aged (>6 weeks) Aβ solutions, a high molecular weight (> 100 000 M(r)) species was detectable in the SEC column void. In contrast to the active monomer, assembled Aβ isolated from the column showed little or no focal association with AD tissue. These studies establish that, at least in vitro, Aβ exists as a monomer at physiological concentrations and that deposition of monomers, rather than of oligomeric Aβ assemblies, mediates the growth of existing amyloid in human brain preparations.

Original languageEnglish (US)
Pages (from-to)10424-10431
Number of pages8
JournalBiochemistry
Volume38
Issue number32
DOIs
StatePublished - Aug 10 1999
Externally publishedYes

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Amyloid Plaques
Amyloid
Size exclusion chromatography
Gel Chromatography
Brain
Alzheimer Disease
Monomers
Molecular Weight
Molecular weight
Growth
Oligomerization
Deposits
Peptides
Dimers
Nuclear magnetic resonance
Association reactions
Tissue
Kinetics
In Vitro Techniques
Therapeutics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Tseng, B. P., Esler, W. P., Clish, C. B., Stimson, E. R., Ghilardi, J. R., Vinters, H. V., ... Maggio, J. E. (1999). Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. Biochemistry, 38(32), 10424-10431. https://doi.org/10.1021/bi990718v

Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. / Tseng, Bertrand P.; Esler, William P.; Clish, Clary B.; Stimson, Evelyn R.; Ghilardi, Joseph R.; Vinters, Harry V.; Mantyh, Patrick W; Lee, Jonathan P.; Maggio, John E.

In: Biochemistry, Vol. 38, No. 32, 10.08.1999, p. 10424-10431.

Research output: Contribution to journalArticle

Tseng, BP, Esler, WP, Clish, CB, Stimson, ER, Ghilardi, JR, Vinters, HV, Mantyh, PW, Lee, JP & Maggio, JE 1999, 'Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations', Biochemistry, vol. 38, no. 32, pp. 10424-10431. https://doi.org/10.1021/bi990718v
Tseng, Bertrand P. ; Esler, William P. ; Clish, Clary B. ; Stimson, Evelyn R. ; Ghilardi, Joseph R. ; Vinters, Harry V. ; Mantyh, Patrick W ; Lee, Jonathan P. ; Maggio, John E. / Deposition of monomeric, not oligomeric, Aβ mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. In: Biochemistry. 1999 ; Vol. 38, No. 32. pp. 10424-10431.
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