A newly designed molecule J2326 for Alzheimer's disease disaggregates amyloid fibrils and induces neurite outgrowth

• Published in: Neuropharmacology 2015-05, Vol.92, p.146-157
• Main Authors: Chang, Pei-Teh, Talekar, Rahul Subhash, Kung, Fan-Lu, Chern, Ting-Rong, Huang, Chen-Wei, Ye, Qing-qing, Yang, Min-Yan, Yu, Chao-Wu, Lai, Shin-Yu, Deore, Ravindra Ramesh, Lin, Jung-Hsin, Chen, Chien-Shu, Chen, Grace Shiahuy, Chern, Ji-Wang
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid - metabolism; Animals; Antipsychotic Agents - chemistry; Antipsychotic Agents - therapeutic use; Chlorides - pharmacology; Disaggregation; Disease Models, Animal; Drug Design; Fatty Alcohols - pharmacology; Mice; Models, Molecular; Neurite outgrowth and neurodegeneration; Neurites - drug effects; Quinolines - pharmacology; Rats; Signal Transduction - drug effects; Zinc - metabolism; Zinc Compounds - pharmacology; β-amyloid
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.01.004

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. [Display omitted] •The newly designed compound owning the properties of clioquinol and long-chain fatty alcohol is synthesized.•The neuritogenic effect of J2326 comes from its 11-carbon alcohol and is enhanced by its 5-chloro-8-methoxyquinoline core.•The molecule targets both zinc-induced and self-aggregated fAβ, whereas clioquinol affects zinc-induced fAβ only.•J2326 reverses neurite collapse and attenuates neurotoxicity in fAβ-driven neurodegeneration in vitro and in vivo.•J2326 restores the learning-based behavior of the hippocampus of fAβ-lesioned mice.