title: A newly designed molecule J2326 for Alzheimer's disease disaggregates amyloid fibrils and induces neurite outgrowth.
abstract: Alzheimer's disease is a neurodegenerative disorder characterized by deposition of β-amyloid (Aβ) fibrils accompanied with progressive neurite loss. None of the clinically approved anti-Alzheimer's agents target both pathological processes. We hypothesized that conjugation of a metal chelator to destabilize Aβ fibrils (fAβs) and a long-chain fatty alcohol to induce neurite outgrowth may generate a novel molecular scaffold that targets both pathologies. The hydroxyalkylquinoline J2326 was designed and synthesized by joining an 11-carbon alcohol to 5-chloro-8-methoxyquinoline at the 2-position and its anti-neurodegenerative potentials in vitro and in vivo were characterized. It attenuated fAβ formation and disaggregated the existing fAβ zinc-dependently as well as zinc-independently. It also triggered extracellular signal-regulated kinase-dependent neurite outgrowth and increased synaptic activity in neuronal cells. In fAβ-driven neurodegeneration in vitro, J2326 reversed neurite collapse and neurotoxicity. These roles of J2326 were also demonstrated in vivo and were pivotal to the observed improvement in memory of mice with hippocampal fAβ lesions. These results show that the effectiveness of J2326 on fAβ-driven neurodegeneration is ascribed to its novel scaffold. This might give clues to evolving attractive therapy for future clinical trials.
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Pei-Teh
authors.initials: PT
authors.lastname: Chang
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Rahul Subhash
authors.initials: RS
authors.lastname: Talekar
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Fan-Lu
authors.initials: FL
authors.lastname: Kung
authors.affiliation: Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, No. 128, Section 2, Academia Road, Taipei, 11529, Taiwan, ROC.
authors.forename: Ting-Rong
authors.initials: TR
authors.lastname: Chern
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Chen-Wei
authors.initials: CW
authors.lastname: Huang
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Ye
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Min-Yan
authors.initials: MY
authors.lastname: Yang
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Chao-Wu
authors.initials: CW
authors.lastname: Yu
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Shin-Yu
authors.initials: SY
authors.lastname: Lai
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC.
authors.forename: Ravindra Ramesh
authors.initials: RR
authors.lastname: Deore
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, No. 128, Section 2, Academia Road, Taipei, 11529, Taiwan, ROC; Institute of Biomedical Sciences, Academia Sinica, No. 128, Section 2, Academia Road, Taipei, 11529, Taiwan, ROC.
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.affiliation: School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.
authors.forename: Chien-Shu
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung, 43301, Taiwan, ROC.
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.affiliation: School of Pharmacy, National Taiwan University, No. 33, Lin-Sen South Road, Taipei, 10051, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin-Ssen South Road, Taipei, 10051, Taiwan, ROC; Department of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei, 10617, Taiwan, ROC. Electronic address: jwchern@ntu.edu.tw.
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D002712:Chlorides / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D005233:Fatty Alcohols / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D016501:Neurites / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000378:metabolism; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D000682:Amyloid; D014150:Antipsychotic Agents; D002712:Chlorides; D005233:Fatty Alcohols; C000603033:J2326 compound; D011804:Quinolines; D017967:Zinc Compounds; C016837:zinc chloride; D015032:Zinc
keywords: Alzheimer's disease; Disaggregation; Neurite outgrowth and neurodegeneration; β-amyloid