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.

Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

“…Chrebp and Srebp2 were each appreciably expressed and unaffected by GVAD, but moderately suppressed by Cyp1b1 deletion. Elsewhere, post-translational SREBP activity has been linked to iron homeostasis through AMPK-directed phosphorylation (Huang et al, 2013, Shah et al, 2016), possibly with different effectiveness for the selective pathway mediators.…”

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain

“…Cultured SH-SY5Y cells were transfected with 200 nM siRNA using Lipofectamine 2000 reagent (Invitrogen) for 24 h [24], then the DMEM medium was replaced with glutamate and anthocyanins as indicated in the respective “Methods” section.…”

Adiponectin Protects against Glutamate‐Induced Excitotoxicity via Activating SIRT1‐Dependent PGC‐1α Expression in HT22 Hippocampal Neurons

“…Notably, one study on the progression of pancreatic cancer showed that APN can protect pancreatic beta cells against apoptosis via activation of 5′ AMP-activated protein kinase (AMPK), SIRT1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ) signaling [28]. Furthermore, modulating the APN receptor 1 (AdipoR1) and inducing AMPK/SIRT1 activation can improve neuropathological deficits in Alzheimer's disease [29]. However, the exact role of SIRT1 in the cytoprotective effects of APN is still not completely understood, especially in cases of stroke.…”