1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose Binds to the N-terminal Metal Binding Region to Inhibit Amyloid β -protein Oligomer and Fibril Formation.

Autor: de Almeida NEC; Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States., Do TD; Department of Chemistry and the Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States., LaPointe NE; Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California 93106, United States., Tro M; Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States., Feinstein SC; Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California 93106, United States., Shea JE; Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States., Bowers MT; Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States.
Jazyk: angličtina
Zdroj: International journal of mass spectrometry [Int J Mass Spectrom] 2017 Sep; Vol. 420, pp. 24-34. Date of Electronic Publication: 2016 Sep 30.
DOI: 10.1016/j.ijms.2016.09.018
Abstrakt: The early oligomerization of amyloid β -protein (A β ) is a crucial step in the etiology of Alzheimer's disease (AD), in which soluble and highly neurotoxic oligomers are produced and accumulated inside neurons. In search of therapeutic solutions for AD treatment and prevention, potent inhibitors that remodel A β assembly and prevent neurotoxic oligomer formation offer a promising approach. In particular, several polyphenolic compounds have shown anti-aggregation properties and good efficacy on inhibiting oligomeric amyloid formation. 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a large polyphenol that has been shown to be effective at inhibiting aggregation of full-length A β 1-40 and A β 1-42 , but has the opposite effect on the C-terminal fragment A β 25-35 . Here, we use a combination of ion mobility coupled to mass spectrometry (IMS-MS), transmission electron microscopy (TEM) and molecular dynamics (MD) simulations to elucidate the inhibitory effect of PGG on aggregation of full-length A β 1-40 and A β 1-42 . We show that PGG interacts strongly with these two peptides, especially in their N-terminal metal binding regions, and suppresses the formation of A β 1-40 tetramer and A β 1-42 dodecamer. By exploring multiple facets of polyphenol-amyloid interactions, we provide a molecular basis for the opposing effects of PGG on full-length A β and its C-terminal fragments.
Competing Interests: Notes The authors declare no competing financial interest.
Databáze: MEDLINE
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