title: Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity.
abstract: Dementia with Lewy bodies (DLB) is a neurodegenerative disorder caused by abnormal accumulation of Lewy bodies, which are intracellular deposits composed primarily of aggregated α-synuclein (αSyn). Although αSyn has been strongly implicated to induce neurotoxicity, overexpression of wild-type αSyn is shown to be insufficient to trigger formation of protein aggregates by itself. Therefore, investigating the possible mechanism underlying αSyn aggregation is essential to understand the pathogenesis of DLB. Previous studies have demonstrated that amyloid β (Aβ), the primary cause of Alzheimer's disease (AD), may promote the formation of αSyn inclusion bodies. However, it remains unclear how Aβ contributes to the deposition and neurotoxicity of αSyn. In the present study, we investigated the cytotoxic effects of Aβ in αSyn-overexpressed neuronal cells. Our results showed that Aβ inhibits autophagy and enhances αSyn aggregation in αSyn-overexpressed cells. Moreover, Aβ also reduced sirtuin 1 (Sirt1) and its downstream signaling, resulting in increased intracellular ROS accumulation and mitochondrial dysfunction. Our in vitro and in vivo studies support that Aβ-inhibition of AMP-activated protein kinase (AMPK) signaling is involved in the neurotoxic effects of αSyn. Taken together, our findings suggest that Aβ plays a synergistic role in αSyn aggregation and cytotoxicity, which may provide a novel understanding for exploring the underlying molecular mechanism of DLB.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung City, Taiwan.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan.
authors.forename: Yu-Shih
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan.
authors.forename: Hsin-Hua
authors.initials: HH
authors.lastname: Li
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Neurology, Show Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Pai-Yi
authors.initials: PY
authors.lastname: Chiu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan.
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: School of Psychology, Chung Shan Medical University, Taichung City, Taiwan; Department of Psychiatry, Chung Shan Medical University Hospital, Taichung City, Taiwan.
authors.forename: Ying-Jui
authors.initials: YJ
authors.lastname: Ho
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Psychiatry, Chung Shan Medical University Hospital, Taichung City, Taiwan. Electronic address: ltj3123@ms2.hinet.net.
authors.forename: Te-Jen
authors.initials: TJ
authors.lastname: Lai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; Amyloid-β; Dementia with Lewy bodies; Sirtuin 1; α-Synuclein