title: Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits.
abstract: Extensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer's disease (AD) pathogenesis. Here, for we believe the first time, we used osmotin, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models. Our results reveal that osmotin treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) activation and reduced SREBP2 (sterol regulatory element-binding protein 2) expression in both in vitro and in vivo AD models and in Adipo-/-mice. Via the AdipoR1/AMPK/SIRT1/SREBP2 signaling pathway, osmotin significantly diminished amyloidogenic Aβ production, abundance and aggregation, accompanied by improved pre- and post-synaptic dysfunction, cognitive impairment, memory deficits and, most importantly, reversed the suppression of long-term potentiation in AD mice. Interestingly, AdipoR1, AMPK and SIRT1 silencing not only abolished osmotin capability but also further enhanced AD pathology by increasing SREBP2, amyloid precursor protein (APP) and β-secretase (BACE1) expression and the levels of toxic Aβ production. However, the opposite was true for SREBP2 when silenced using small interfering RNA in APPswe/ind-transfected SH-SY5Y cells. Similarly, osmotin treatment also enhanced the non-amyloidogenic pathway by activating the α-secretase gene that is, ADAM10, in an AMPK/SIRT1-dependent manner. These results suggest that osmotin or osmotin-based therapeutic agents might be potential candidates for AD treatment.
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Shah
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: G H
authors.initials: GH
authors.lastname: Yoon
authors.affiliation: Department of Physiology, College of Medicine, Yonsei University, Seoul, Republic of Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: M N
authors.initials: MN
authors.lastname: Abid
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: T H
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Division of Life Science and Applied Life Science (BK21 Plus), College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: M O
authors.initials: MO
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D010940:Plant Proteins / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D054419:Receptors, Adiponectin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D056564:Sirtuin 1 / Q000187:drug effects; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010940:Plant Proteins; D054419:Receptors, Adiponectin; D051782:Sterol Regulatory Element Binding Protein 2; C073139:osmotin protein, Nicotiana tabacum; D055372:AMP-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D056564:Sirtuin 1