title: Z-Phe-Ala-diazomethylketone (PADK) disrupts and remodels early oligomer states of the Alzheimer disease Aβ42 protein.
abstract: The oligomerization of the amyloid-β protein (Aβ) is an important event in Alzheimer disease (AD) pathology. Developing small molecules that disrupt formation of early oligomeric states of Aβ and thereby reduce the effective amount of toxic oligomers is a promising therapeutic strategy for AD. Here, mass spectrometry and ion mobility spectrometry were used to investigate the effects of a small molecule, Z-Phe-Ala-diazomethylketone (PADK), on the Aβ42 form of the protein. The mass spectrum of a mixture of PADK and Aβ42 clearly shows that PADK binds directly to Aβ42 monomers and small oligomers. Ion mobility results indicate that PADK not only inhibits the formation of Aβ42 dodecamers, but also removes preformed Aβ42 dodecamers from the solution. Electron microscopy images show that PADK inhibits Aβ42 fibril formation in the solution. These results are consistent with a previous study that found that PADK has protective effects in an AD transgenic mouse model. The study of PADK and Aβ42 provides an example of small molecule therapeutic development for AD and other amyloid diseases.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, USA.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.forename: Megan M
authors.initials: MM
authors.lastname: Gessel
authors.forename: Meagan L
authors.initials: ML
authors.lastname: Wisniewski
authors.forename: Kishore
authors.initials: K
authors.lastname: Viswanathan
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D012995:Solubility / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C015795:diazomethyl ketones; D003978:Diazomethane; C022922:carbobenzoxycarbonyl-L-phenylalanyl-L-alanine-D-diazomethane