%0 Journal Article
%T Apolipoprotein E: Isoform Specific Differences in Tertiary Structure and Interaction with Amyloid-¦Â in Human Alzheimer Brain
%A Phillip B. Jones
%A Kenneth W. Adams
%A Anete Rozkalne
%A Tara L. Spires-Jones
%A Tammy T. Hshieh
%A Tadafumi Hashimoto
%A Christine A. F. von Armin
%A Mathew Mielke
%A Brian J. Bacskai
%A Bradley T. Hyman
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0014586
%X We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in A¦Â-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with A¦Â than ApoE4, but a greater proportion of A¦Â molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with A¦Â deposition. We found an increased number of ApoE N-terminal fragments in ApoE4 plaques, consistent with the observation that ApoE4 is more easily cleaved than ApoE3. In addition, we measured a small but significant isoform specific difference in ApoE domain interaction. Based on our in situ data, supported by traditional biochemical data, we propose a pathway by which isoform specific conformational differences increase the level of cleavage at the hinge region of ApoE4, leading to a loss of ApoE function to mediate clearance of A¦Â and thereby increase the risk of AD for carriers of the APOE¦Å4 allele.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014586