SDS-Stable Complex Formation between Native Apolipoprotein E3 and -Amyloid Peptides
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- 作者：Gregory W. Munson ; Alex E. Roher ; Yu-Min Kuo ; Sean M. Gilligan ; Catherine A. Reardon ; Godfrey S. Getz ; and Mary Jo LaDu
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：December 26, 2000
- 年：2000
- 卷：39
- 期：51
- 页码：16119 - 16124
- 全文大小：123K
- 年卷期：v.39,no.51(December 26, 2000)
- ISSN：1520-4995
文摘
Extracellular senile plaques composed predominantly of fibrillar amyloid-
(A) are a majorneuropathological feature of Alzheimer's disease (AD). Genetic evidence and in vivo studies suggest thatapolipoprotein E (apoE) may contribute to amyloid clearance and/or deposition. In vitro studies demonstratethat native apoE2 and E3 form an SDS-stable complex with A(1-40), while apoE4 forms little suchcomplex. Our current work extends these observations by presenting evidence that apoE3 also binds toA(1-42) and with less avidity to modified species of the peptide found in senile plaque cores. Thesemodified peptides include a form that originates at residue 3-Glu as pyroglutamyl and another withisomerization at the 1-Asp and 7-Asp positions. In addition, we used binding reactions between apoE3and various A fragments, as well as binding reactions with apoE3 and A(1-40) plus A fragments ascompetitors, to identify the domain(s) of A involved in the formation of an SDS-stable complex withapoE3. Residues 13-28 of A appear to be necessary, while complex formation is further enhanced bythe presence of residues at the C-terminus of the peptide. These results contribute to our understandingof the biochemical basis for the SDS-stable apoE3/A complex and support the hypothesis that A canbe transported in vivo complexed with apoE. This complex may then be cleared from the interstitialspace by apoE receptors in the brain or become part of an extracellular amyloid deposit.
(A) are a majorneuropathological feature of Alzheimer's disease (AD). Genetic evidence and in vivo studies suggest thatapolipoprotein E (apoE) may contribute to amyloid clearance and/or deposition. In vitro studies demonstratethat native apoE2 and E3 form an SDS-stable complex with A(1-40), while apoE4 forms little suchcomplex. Our current work extends these observations by presenting evidence that apoE3 also binds toA(1-42) and with less avidity to modified species of the peptide found in senile plaque cores. Thesemodified peptides include a form that originates at residue 3-Glu as pyroglutamyl and another withisomerization at the 1-Asp and 7-Asp positions. In addition, we used binding reactions between apoE3and various A fragments, as well as binding reactions with apoE3 and A(1-40) plus A fragments ascompetitors, to identify the domain(s) of A involved in the formation of an SDS-stable complex withapoE3. Residues 13-28 of A appear to be necessary, while complex formation is further enhanced bythe presence of residues at the C-terminus of the peptide. These results contribute to our understandingof the biochemical basis for the SDS-stable apoE3/A complex and support the hypothesis that A canbe transported in vivo complexed with apoE. This complex may then be cleared from the interstitialspace by apoE receptors in the brain or become part of an extracellular amyloid deposit.