title: The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation.
abstract: Missense mutations in alanine 673 of the amyloid precursor protein (APP), which corresponds to the second alanine of the amyloid β (Aβ) sequence, have dramatic impact on the risk for Alzheimer disease; A2V is causative, and A2T is protective. Assuming a crucial role of amyloid-Aβ in neurodegeneration, we hypothesized that both A2V and A2T mutations cause distinct changes in Aβ properties that may at least partially explain these completely different phenotypes. Using human APP-overexpressing primary neurons, we observed significantly decreased Aβ production in the A2T mutant along with an enhanced Aβ generation in the A2V mutant confirming earlier data from non-neuronal cell lines. More importantly, thioflavin T fluorescence assays revealed that the mutations, while having little effect on Aβ42 peptide aggregation, dramatically change the properties of the Aβ40 pool with A2V accelerating and A2T delaying aggregation of the Aβ peptides. In line with the kinetic data, Aβ A2T demonstrated an increase in the solubility at equilibrium, an effect that was also observed in all mixtures of the A2T mutant with the wild type Aβ40. We propose that in addition to the reduced β-secretase cleavage of APP, the impaired propensity to aggregate may be part of the protective effect conferred by A2T substitution. The interpretation of the protective effect of this mutation is thus much more complicated than proposed previously.
authors.affiliation: From the VIB Center for the Biology of Disease, the Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven.
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.affiliation: the VIB Switch Laboratory, the Switch Laboratory, Department of Cellular and Molecular Medicine.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: Laboratory of Solid State Physics and Magnetism, University of Leuven, 3000 Leuven, and Imec, 3001 Leuven, Belgium.
authors.forename: Andreea-Alexandra
authors.initials: AA
authors.lastname: Ungureanu
authors.affiliation: the VIB Switch Laboratory, the Switch Laboratory, Department of Cellular and Molecular Medicine.
authors.forename: Virginia
authors.initials: V
authors.lastname: Castillo Cano
authors.affiliation: From the VIB Center for the Biology of Disease, the Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven.
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.affiliation: the VIB Switch Laboratory, the Switch Laboratory, Department of Cellular and Molecular Medicine.
authors.forename: Meine
authors.initials: M
authors.lastname: Ramakers
authors.affiliation: Laboratory of Solid State Physics and Magnetism, University of Leuven, 3000 Leuven, and Imec, 3001 Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Bartic
authors.affiliation: the VIB Switch Laboratory, the Switch Laboratory, Department of Cellular and Molecular Medicine.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: the VIB Switch Laboratory, the Switch Laboratory, Department of Cellular and Molecular Medicine.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: From the VIB Center for the Biology of Disease, the Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, bart.destrooper@cme.vib-kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; D053829:Amyloid Precursor Protein Secretases
keywords: Aggregation; Alzheimer Disease; Amyloid-β (Aβ); Kinetics; Thermodynamics