Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer’s disease neuropathological deficits

作者：Sonia Shah, Gayoung Yoon, Seungsoo Chung, Noman Bin Abid, Tae Hoon Kim, H Y Lee, M O Kim · 发表于：Molecular Psychiatry · 年份：2016 · DOI：10.1038/mp.2016.23 · 被引用次数：211 · 研究领域：Sirtuins and Resveratrol in Medicine、Adipose Tissue and Metabolism、Adipokines, Inflammation, and Metabolic Diseases

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-de...