title: Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.
abstract: In Alzheimer's disease (AD), most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed overexpression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study, in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP, with Kd = 86±9 μM. In cultured cells expressing both proteins, the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase, significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1, these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.
authors.affiliation: Janssen Research & Development, LLC, Johnson & Johnson, San Diego, CA, USA.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb, Biologics Process Development, Devens, MA, USA.|Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Sanders
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Buxbaum
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011228:Prealbumin / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011228:Prealbumin; D053829:Amyloid Precursor Protein Secretases
keywords: APP; APP23; Alzheimer’s disease; Aβ; AβPP; gamma secretase; nuclear magnetic resonance; phosphorylation; transthyretin