Osmotin as a Novel Drug for the Prevention of Alzheimer's Disease

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).

Fluorescence images of (d) Aβ plaques and (e) Aβ aggregates in the cortex and hippocampus of 12- and 16-month old APP mice. Accompanied by relative protein density histograms showing significant reduction in Aβ density after osmotin treatment. Osmotin was administered over 4 weeks.
Figure 1. Fluorescence images of (d) Aβ plaques and (e) Aβ aggregates in the cortex and hippocampus of 12- and 16-month old APP mice. Accompanied by relative protein density histograms showing significant reduction in Aβ density after osmotin treatment. Osmotin was administered over 4 weeks.

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.

Reference:

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.

11 Replies to “Osmotin as a Novel Drug for the Prevention of Alzheimer's Disease”

  1. wow, what an interesting article with potentially huge implications!

    I thought it was interesting that the authors mention they have previously shown that osmotin has a similar protective effect on neurodegeneration in glutamate and ethanol toxicity. This led me to think perhaps the mechanisms outlined in this article relative to AD and cholesterol may simply be generally neuroprotective mechanisms and not only AD specific and AB mediating. Did you read anything that might (not) support this idea? If so, how does this implicate the findings of it as a potential treatment for AD?

    1. I’m glad you noticed that Elaine, I would agree that because it agonizes a hormone receptor the effects of osmotin here are more generally metabolic and not AD specific. Deficiency in adiponectin is associated with metabolic syndrome such as Type II Diabetes: (10.1111/j.1463-1326.2005.00510.x). In class we learned about the link between insulin resistance and AD. I think as our understanding of the connections between Alzheimer’s disease and metabolic syndrome grow we will better understand the neuroprotective mechanism of osmotin. Exciting stuff!

  2. Great article Elliott! My question is in regards to the cotreatment of the human neuronal cells with Aβ and osmotin. You mentioned that treating together produced more viable cells than treatment with just Aβ; however, I am wondering how treating with just Aβ would help the neuronal cells at all because the buildup of these is what causes the formation of the insoluble plaques? After seeing the mention of just this treatment, I questioned if the authors conducted a trial with solely osmotin and compared that to the combination of osmotin and Aβ. How would this method compare with treating the cells with just Aβ?

    1. Hey Tyler, to my understanding treatment with Aβ wasn’t really intended to help the neuronal cells but rather mimic Alzheimer’s disease by depositing as plaques. The authors did not run any trials with just osmotin (and no Aβ), but I agree it would be interesting to see if osmotin alone could cause any significant survival difference from WT neurons. Although because the authors are exploring Alzheimer’s disease, I think they were only really interested in how osmotin could exert its effects in the presence of Aβ plaques.

  3. Really well written Elliot. To expand on Elaine’s thoughts that osmotin acts as a general neuroprotective, based on the previous research done by the author, but couldn’t an osmotin based drug also be used as a preventative treatment for heart disease and other high cholesterol related diseases, as it reduces cholesterol through regulation of AMPK which is expressed in all organs? The link between osmotin, cholesterol regulation, and heart disease is more clear and direct; I’m wondering if research into osmotin began there and has expanded to this research as a neuroprotective.

    1. Thanks Zach, osmotin will mimic the effects of adiponectin in any cell expressing adiponectin receptors. I think that (just based on publication dates) this research began as osmotin was identified as an adiponectin receptor agonist and built on previous research into adiponectin signaling, which is extensive. However I don’t really know for sure how knowledge about osmotin has developed over the years.

      Adiponectin agonism has a wide scope of therapeutic potential. If you scroll down on this page, there’s a really great figure depicting the various downstream pathways of adiponectin receptors, which osmotin agonizes: https://www.biomol.de/adiponectin.html?id=1301

  4. Awesome paper Elliott and great explanation. It’s really cool how you connected so many aspects that have been covered in our course so far: Aβ plaques in Alzheimer’s Disease, it’s connection to cholesterol synthesis and regulation, as well as sirtuins acting as regulators in metabolism. What I want to know is why osmotin was the hormone chosen for this experiment? Also, how does the fact that it is from a plant implicate the relationship between plant and animal hormones and cholesterol?

    1. Hey Stephanie, I believe osmotin was chosen simply because it is structurally and functionally similar to adiponectin. In animals adiponectin regulates the AMPK/SIRT1 pathway to control metabolism, but in plants osmotin actually acts as an antimicrobial defense mechanism in response to stress. Plants also lack cholesterol and so I doubt that osmotin and adiponectin evolved this similarly for any reason besides chance. However not a lot of research exists about the mechanism of osmotin, so hopefully there is a lot more to learn!

      If you’re interested, here is a paper about adiponectin receptors identifying osmotin as an AdipoR agonist: http://dx.doi.org/10.1210/er.2005-0005#sthash.91fiKfDO.dpuf

  5. I thoroughly enjoyed your post Elliot! I actually wrote a paper earlier in the semester about an article that was retracted for altered data on how SIRT1 activates ADAM10, so it was nice to see that someone else showed this in an actually ethical way!

    Did you come across anything in your research that indicates that the authors have or will looked at the effect of osmotin on other neurodegenerative diseases besides AD? If it activates AMPK and SIRT1, and those proteins are also involved in neurodegenerative diseases, then osmotin could be a golden drug therapy. However, if those proteins are not, do you think someone in the field might look at other plant molecules as well?

    1. Thanks Nikki. I know this research group has published previously on osmotin’s neuroprotective effects against glutamate-induced (excitotoxic) neurodegeneration and ROS production (10.1038/cddis.2013.538). Activation of AMPK regulates energy dynamics in a variety of ways, including mitochondrial regulation and autophagy, which carries implications for a variety of neurodegenerative diseases. There is only a bit of research on the neuroprotective effects of osmotin specifically, and it’s mostly from the last 2 years, but I’m sure it is growing! It would be interesting to see other cases in which osmotin is neuroprotective, that research has yet to be done.

  6. Hey Elliot, a very interesting read and its great to discover more about A.D. The last time I researched A.D. was for a NSC Brain and Behavior paper. I recall how the accumulation of amyloid-β proteins was a significant problem for patients and researchers were investigating them. I found this blog to be very interesting. The development of osmotin as a means to express AMPK and SIRT1 and control amyloid-β production is incredible and a significant step forward. With the over-expression of AMPK and SIRT1, do the authors notice any adverse side effects in the mice they were treating? Also, since this drug sounds like a very promising lead and with more pressure coming form the medical community for new A.D. drugs, do the authors elaborate on when they exprect to conduct human trials?

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