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All That Glitters and Cures

The story of King Midas in Greek mythology perfectly illustrates our fascination with gold. In that story, Midas wished that everything would turn into gold upon his touch. His wish was granted, and he died because of it—because his food would also turn into gold, poor Midas died of starvation. As the story shows, our desire to possess gold has been with us since ancient times, and even though gold’s value has somewhat diminished in our time, gold still represents wealth and security in many countries. Even research biologists are not immune to the allure of gold. Though for them, the appeal of gold lies elsewhere: gold nanoparticles are not toxic to the cells and drugs can be added to these nanoparticles to ensure effective delivery. In their paper published in 2016, Alex Savchenko and his colleagues described one such use of gold nanoparticles. They creatively used gold nanoparticles to solve a complex delivery problem. An analogy of what they attempted to achieve would be to be able to brush in a way that the toothpaste and brush only touch one tooth. How did they do it?

To appreciate their ideas, we need to understand some physical features of a neuron. We can think of a typical neuron as a human body where the hands represent neuron’s ‘dendrites’, the head and the torso neuronal ‘cell body’, and the legs ‘axons’. Since neurons have several dendrites and only one axon, a closer approximation would be to picture someone with multiple hands and only one leg, but we’ll stick to the typical human body analogy for simplicity. If we now imagine a person is standing on another person’s palms, we have two human-neurons that are almost set for neuronal communication. The point the axon terminal from one neuron meets the dendrites from another neuron—that is where the feet meet the palm in our analogy—is called a synapse. Even though we imagined the feet are touching the palms here, to communicate, neurons don’t need physical contact. Instead, at the synapse, the axons terminals don’t touch the dendrites (imagine the feet hanging just above the palm without touching it). There is, thus, a small gap between the axon terminals and dendrites at the synapse, and this gap is called synaptic cleft.

When the first neuron sends a nerve impulse, the electrochemical signal travels through the axon and arrives at the axon terminals. Axon endings or terminals then release some chemicals that travel through the synaptic cleft to bind to the receivers located on the dendrites. These receivers are called receptors. The binding of these chemicals to the receptors can enable the second neuron to create its own nerve impulse. And this would go on to the third neuron and eventually to other neurons connected in that network.

There are various types of receptors because they bind to different types of chemicals, and NMDA (N-methyl-D-aspartate) receptors, the ones the researchers focused on here, are one such receptor class. NMDA receptors are also ion channels or pores because under appropriate conditions—such as when right compound binds to it—they open up to let certain ions[1] to flow into the neurons. While NMDA receptors located at the synapses play a vital role in neuronal communication, these receptors can be found elsewhere as well. Interestingly, at the synapse, activities of NMDA receptors seem to stimulate neuronal survival whereas activities of NMDA receptors located elsewhere seem to stimulate cell death. In the paper, the scientists used gold nanoparticles to block the activity of the latter group of receptors without interfering NMDA receptors’ activities at the synapse. But how can you selectively target only one group of those receptors? And is it even possible to block any receptor?

The answer to the last question is yes. There is an FDA-approved drug for treating Alzheimer’s disease named memantine. Memantine can bind to the NMDA receptors, but it can’t open the channels (pores remain closed). Moreover, when memantine is bound to the NMDA receptors, the compound that naturally binds to the receptors can no longer bind because the binding site is now occupied by memantine. So when memantine is present, ions can’t flow into the neurons through the NMDA receptors. Memantine thus blocks NMDA receptor activity and interferes with neuronal communication.

This is where the gold nanoparticles come in: to selectively block NMDA receptors located outside the synapses, the researchers linked memantine to gold nanoparticles. They took advantage of the fact that synaptic clefts are very tiny. On average, they are about 25nm wide (a sheet of paper, in contrast, is 100,000nm thick!). They reasoned that if they could somehow make a memantine compound that is bigger than 25nm, it won’t fit into the synaptic cleft and hence, won’t interfere with the synaptic NMDA receptors. To achieve this, they coated gold nanoparticles—about 10nm in diameter—with chemical linkers and then added memantine to those linkers. The finished product was about 35nm in diameter, too big to fit into the synaptic cleft. It looks similar to a ripe, round avocado that has been stuck with many lollipops. The seed here represents the gold nanoparticle, avocado flesh the linkers, and the edible parts of the lollipops, memantine.

The researchers did several experiments to show that this gold-memantine compound didn’t block synaptic NMDA receptors or neuronal communication but could block the NMDA receptors located elsewhere. Here, I will go over one of these experiments. In one experiment, they showed that when the whole neuron is exposed—that is there is no synaptic cleft—it’s possible to make the neuron send a nerve impulse with the compound that activates the NMDA receptors physiologically. Both memantine and memantine-gold blocked this because both compounds could reach all the NMDA receptors located on that neuron. However, when a neuron created a nerve impulse naturally, free memantine could block that impulse whereas gold-memantine couldn’t. In other words, unlike the gold-memantine compound, free memantine was small enough to go into the synaptic cleft to block signal transmission.

They also showed that some cultured neurons, NMDA application could kill the neurons (NMDA receptors got their name because NMDA compound can artificially open up these receptors/channels). Compared to free memantine, the gold-memantine compound was significantly more effective in protecting neurons under NMDA-induced cell toxicity. Similarly, on freshly cut brain slices, the gold-memantine compound protected neurons better than memantine when the slices were deprived of glucose and oxygen, similar to what happens in a brain stroke.

Finally, the researchers looked into the effectiveness of memantine versus gold-memantine on an Alzheimer ’s disease model. One feature of the disease is that the dendritic spines—this is where the axon terminals form synapses—disappears. This loss of synaptic spines can be replicated on brain slice preparations where neurons stay alive for days: treating the slices with a particular toxic chemical can significantly reduce the number/density of these synaptic spines. In this experimental setup, gold-memantine treated slices had similar dendritic spine density compared to the control where no toxic chemical was added. Free memantine did reduce the loss, but it was significantly less effective than the gold-memantine compound. These results suggest that the gold-memantine compound potentially could be more effective in treating Alzheimer’s disease than memantine.

Of course, more experiments need to be done before the FDA approves this gold-memantine compound to treat Alzheimer’s disease. For starters, we need to see if the compound has any harmful effect on animals. Also, while the authors did mention that compound bulkier than the gold-memantine compound could cross the blood-brain barrier, they didn’t show if gold-memantine could. They did show that on thick brain slices, this compound can diffuse through the tissue, but that doesn’t prove that the compound can diffuse through the entire brain. Perhaps—as the researchers have suggested—the gold-memantine compound can be administered locally, but that would be much more complicated than simply taking a pill. But these concerns or questions are less significant compared to the ingenuity the researchers have shown here: their research could very well be adopted for not only treating Alzheimer’s disease but also for treating neurodegenerative diseases in general.

[1] I will write another essay that goes more into ions.

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