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: S A Shah, G H Yoon, S S Chung, M N Abid, T H Kim, H Y Lee, M O Kim
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 22 Issue 3 Pg. 407-416 (03 2017) ISSN: 1476-5578 [Electronic] England
• PMID: 27001618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Plant Proteins
• Receptors, Adiponectin
• Sterol Regulatory Element Binding Protein 2
• osmotin protein, Nicotiana tabacum
• AMP-Activated Protein Kinases
• Amyloid Precursor Protein Secretases
• Sirtuin 1

Topics

• AMP-Activated Protein Kinases (drug effects)
• Alzheimer Disease (drug therapy, genetics, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Disease Models, Animal
• Humans
• Long-Term Potentiation (physiology)
• Memory Disorders (genetics)
• Mice
• Mice, Transgenic
• Phosphorylation
• Plant Proteins (pharmacology, physiology, therapeutic use)
• Receptors, Adiponectin (drug effects, metabolism)
• Signal Transduction (genetics)
• Sirtuin 1 (drug effects)
• Sterol Regulatory Element Binding Protein 2 (antagonists & inhibitors, drug effects, metabolism)