Alzheimer’s disease is a progressive brain disorder that impairs cognitive function and destroys memory in older adults. It is characterized even in its earliest stages by an accumulation of amyloid-β proteins (Aβ), which form insoluble plaques between neurons in the brain. The disease also affects cholesterol homeostasis, or the ability of the body to balance cholesterol levels. Noticing that this abnormal neuronal metabolism results in increased production of Aβ, Shah et al. recently explored the relationship of Alzheimer’s disease to metabolism using osmotin, a plant protein which they show to reduce cholesterol biosynthesis and halt the progression of Alzheimer’s disease.
Osmotin protects the tobacco plant from bacteria. Interestingly, it is similar to the animal hormone adiponectin, which controls energy metabolism through the two proteins AMPK and SIRT1. AMPK works by sensing cellular energy—when energy is low, AMPK phosphorylates certain proteins that stimulate energy-producing pathways and deactivate energy-consuming pathways. In this way, AMPK activity manages cellular energy homeostasis. SIRT1 is the most well-known member of a group of proteins called sirtuins, which sense the availability of nutrients within the cell and regulate the expression of genes involved in metabolism. AMPK and SIRT1 act in a coordinated way to maintain normal energy metabolism, and both are controlled by the activity of adiponectin at receptors called AdipoR1. In this study, the authors explore this AdipoR1/AMPK/SIRT1 pathway in Alzheimer’s disease by treatment with osmotin, a plant-derived mimic of adiponectin.
The authors first investigated the cotreatment of Aβ and osmotin in human neuronal cells and found that cells treated with both Aβ and osmotin were significantly more viable than those treated with Aβ alone. They further explored this phenomenon by looking at the expression of AdipoR1 adiponectin receptors in Adipo-/- mice, which are genetically engineered to lack adiponectin. When Adipo-/- mice were treated with osmotin, AdipoR1 was more highly expressed, increasing AMPK and SIRT1 and inhibiting production of Aβ proteins. The authors were able to conclude that osmotin induced the activation of AMPK and SIRT1 by treating cells with Aβ to inhibit expression of AMPK and SIRT1, showing that with osmotin treatment these inhibitory effects of Aβ could be reversed. To explore the implications of osmotin for abnormal neuronal metabolism, they next examined cholesterol and triglyceride levels in APP and Adipo-/- mice. Osmotin treatment significantly reduced the levels of total cholesterol, LDL, and triglyceride, while increasing the levels of HDL. The authors show that this reduction in cholesterol results from osmotin reducing the levels of SREBP2, a protein that upregulates cholesterol biosynthesis. In order to examine the effects of osmotin on Aβ levels in the brain, mouse brains were stained with Aβ antibodies, which dye Aβ proteins for visual evaluation. Osmotin-treated APP mice exhibited a significant decrease in Aβ deposits compared to control APP mice after 4 weeks of osmotin administration (Figure 1).
The effects of osmotin in reducing the buildup of Aβ plaques imply its usefulness as a treatment for Alzheimer’s disease. In the brain, long-term potentiation is the strengthening of synapses to produce long-lasting connection between neurons. Long-term potentiation is implicated in memory and is significantly suppressed in APP mice compared with wild-type mice. APP mice treated with osmotin experienced a restoration of long-term potentiation to within error of the wild-type level, indicating that osmotin had restored the ability to restore functional synapses in an Alzheimer’s disease phenotype. Finally, to study the role of osmotin in memory and cognition, wild-type, APP and APP/osmotin-treated mice were subjected to cognitive tests of general and spatial memory function. The APP mice in both tests showed less working memory capacity, a deficit which was significantly reduced by treatment with osmotin. By exploring the role of osmotin in improving synapses, reducing cholesterol biosynthesis, and restoring memory and cognition, Shah et al. give the first report on the beneficial effects of osmotin activating AMPK and SIRT1 and inhibiting SREBP2 to block the pathway of Aβ production. In the quest to curb Alzheimer’s disease, osmotin is a very promising preventative therapy.
Shah, S A, G H Yoon, S S Chung, M N Abid, T H Kim, H Y Lee, and M O Kim. 2016. “Novel Osmotin Inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 Pathway to Improve Alzheimer’s Disease Neuropathological Deficits.” Molecular Psychiatry, March. doi:10.1038/mp.2016.23.