title: Alzheimer's amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity.
abstract: Alzheimer's disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-β peptide (Aβ). Several familial mutations found in Aβ sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aβ, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aβ shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aβ40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aβ, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Aβ. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aβ fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Aβ aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Tien-Wei
authors.initials: TW
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Fon
authors.initials: CF
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Liao
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002942:Circular Dichroism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D016229:Amyloid beta-Peptides