title: Phosphorylation at Ser8as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue β-Amyloid (Aβ40) Fibrils.
abstract: Polymorphism of amyloid-β (Aβ) fibrils, implying different fibril structures, may play important pathological roles in Alzheimer's disease (AD). Morphologies of Aβ fibrils were found to be sensitive to fibrillation conditions. Herein, the Ser8-phosphorylated Aβ (pAβ), which is assumed to specially associate with symptomatic AD, is reported to modify the morphology, biophysical properties, cellular toxicity, and structures of Aβ fibrils. Under the same fibrillation conditions, pAβ favors the formation of fibrils (Fpβ), which are different from the wild-type Aβ fibrils (Fβ). Both Fβand Fpβfibrils show single predominant morphologies. Compared with Fβ, Fpβexhibits higher propagation efficiency and higher neuronal cell toxicity. The residue-specific structural differences between the Fβ- and Fpβ-seeded Aβ fibrils were identified using magic angle spin NMR. Our results suggest a potential regulatory mechanism of phosphorylation on Aβ fibril formation in AD and imply that the post-translationally modified Aβ, especially the phosphorylated Aβ, may be an important target for the diagnosis or treatment of AD at specific stages.
authors.affiliation: From the Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Zhi-Wen
authors.initials: ZW
authors.lastname: Hu
authors.affiliation: From the Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Meng-Rong
authors.initials: MR
authors.lastname: Ma
authors.affiliation: From the Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Chen
authors.affiliation: From the Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Binghamton University, State University of New York, Binghamton, New York 13902, and wqiang@binghamton.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.affiliation: From the Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China, liym@mail.tsinghua.edu.cn.|Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D011487:Protein Conformation; D012694:Serine / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D012694:Serine
keywords: Alzheimer's disease; amyloid; fibril; morphology; phosphorylation; solid state NMR; structure