Deposition of Monomeric, Not Oligomeric, A Mediates Growth of Alzheimer's Disease Amyloid Plaques in Human Brain Prep
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- 作者：Bertrand P. Tseng ; William P. Esler ; Clary B. Clish ; Evelyn R. Stimson ; Joseph R. Ghilardi ; Harry V. Vinters ; Patrick W. Mantyh ; Jonathan P. Lee ; and John E. Maggio
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：August 10, 1999
- 年：1999
- 卷：38
- 期：32
- 页码：10424 - 10431
- 全文大小：106K
- 年卷期：v.38,no.32(August 10, 1999)
- ISSN：1520-4995
文摘
Senile plaques composed of the peptide A
beta2.gif" BORDER=0 ALIGN="middle"> contribute to the pathogenesis of Alzheimer'sdisease (AD), and mechanisms underlying their formation and growth may be exploitable as therapeutictargets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusionchromatography (SEC), translational diffusion measured by NMR, and in vitro models of Abeta2.gif" BORDER=0 ALIGN="middle"> amyloidgrowth to identify the oligomerization state of Abeta2.gif" BORDER=0 ALIGN="middle"> that is competent to add onto an existing amyloiddeposit. SEC of radiolabeled and unlabeled Abeta2.gif" BORDER=0 ALIGN="middle"> over a concentration range of 10-10-10-4 M demonstratedthat the freshly dissolved peptide eluted as a single low molecular weight species, consistent with monomeror dimer. This low molecular weight Abeta2.gif" BORDER=0 ALIGN="middle"> species isolated by SEC was competent to deposit onto preexistingamyloid in preparations of AD cortex, with first-order kinetic dependence on soluble Abeta2.gif" BORDER=0 ALIGN="middle"> concentration,establishing that solution-phase oligomerization is not rate limiting. Translational diffusion measurementsof the low molecular weight Abeta2.gif" BORDER=0 ALIGN="middle"> fraction demonstrate that the form of the peptide active in plaque depositionis a monomer. In deliberately aged (>6 weeks) Abeta2.gif" BORDER=0 ALIGN="middle"> solutions, a high molecular weight (>100 000 Mr)species was detectable in the SEC column void. In contrast to the active monomer, assembled Abeta2.gif" BORDER=0 ALIGN="middle"> isolatedfrom the column showed little or no focal association with AD tissue. These studies establish that, at leastin vitro, Abeta2.gif" BORDER=0 ALIGN="middle"> exists as a monomer at physiological concentrations and that deposition of monomers, ratherthan of oligomeric Abeta2.gif" BORDER=0 ALIGN="middle"> assemblies, mediates the growth of existing amyloid in human brain preparations.
beta2.gif" BORDER=0 ALIGN="middle"> contribute to the pathogenesis of Alzheimer'sdisease (AD), and mechanisms underlying their formation and growth may be exploitable as therapeutictargets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusionchromatography (SEC), translational diffusion measured by NMR, and in vitro models of Abeta2.gif" BORDER=0 ALIGN="middle"> amyloidgrowth to identify the oligomerization state of Abeta2.gif" BORDER=0 ALIGN="middle"> that is competent to add onto an existing amyloiddeposit. SEC of radiolabeled and unlabeled Abeta2.gif" BORDER=0 ALIGN="middle"> over a concentration range of 10-10-10-4 M demonstratedthat the freshly dissolved peptide eluted as a single low molecular weight species, consistent with monomeror dimer. This low molecular weight Abeta2.gif" BORDER=0 ALIGN="middle"> species isolated by SEC was competent to deposit onto preexistingamyloid in preparations of AD cortex, with first-order kinetic dependence on soluble Abeta2.gif" BORDER=0 ALIGN="middle"> concentration,establishing that solution-phase oligomerization is not rate limiting. Translational diffusion measurementsof the low molecular weight Abeta2.gif" BORDER=0 ALIGN="middle"> fraction demonstrate that the form of the peptide active in plaque depositionis a monomer. In deliberately aged (>6 weeks) Abeta2.gif" BORDER=0 ALIGN="middle"> solutions, a high molecular weight (>100 000 Mr)species was detectable in the SEC column void. In contrast to the active monomer, assembled Abeta2.gif" BORDER=0 ALIGN="middle"> isolatedfrom the column showed little or no focal association with AD tissue. These studies establish that, at leastin vitro, Abeta2.gif" BORDER=0 ALIGN="middle"> exists as a monomer at physiological concentrations and that deposition of monomers, ratherthan of oligomeric Abeta2.gif" BORDER=0 ALIGN="middle"> assemblies, mediates the growth of existing amyloid in human brain preparations.