title: Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain.
abstract: We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in Aβ-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with Aβ than ApoE4, but a greater proportion of Aβ molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with Aβ 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 Aβ and thereby increase the risk of AD for carriers of the APOEε4 allele.
authors.affiliation: Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Jones
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Adams
authors.forename: Anete
authors.initials: A
authors.lastname: Rozkalne
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.forename: Tammy T
authors.initials: TT
authors.lastname: Hshieh
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Armin
authors.forename: Mathew
authors.initials: M
authors.lastname: Mielke
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D053318:Apolipoprotein E3 / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000378:metabolism; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D058225:Plaque, Amyloid / Q000473:pathology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms