apolipoprotein e isoform specific differences in tertiary structure and interaction with amyloid-β in human alzheimer brain载脂蛋白e异构体三级结构的具体差异和互动amyloid-β人类大脑老年痴呆症.pdfVIP

Apolipoprotein E: Isoform Specific Differences in Tertiary Structure and Interaction with Amyloid-b in Human Alzheimer Brain 1 1 1 1 1 Phillip B. Jones , Kenneth W. Adams , Anete Rozkalne , Tara L. Spires-Jones , Tammy T. Hshieh , 1 2 1 1 1 Tadafumi Hashimoto , Christine A. F. von Armin , Mathew Mielke , Brian J. Bacskai , Bradley T. Hyman * 1 Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America, ¨ ¨ 2 Klinik fur Neurologie, Universitatsklinikum Ulm, Ulm, Germany Abstract We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in Ab-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with Ab than ApoE4, but a greater proportion of Ab molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with Ab 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 Ap