A tiny ball of gold carrying medicine could help doctors fight Alzheimer’s disease. Scientists have created a nanoparticle that is just the right size to target the overactive brain receptors that cause neurological disease, while leaving the rest of the receptors we need alone. This super-precise method could reduce the side effects of a common Alzheimer’s drug so doctors can prescribe it to help people during earlier stages of the condition.
Neurological problems can be caused by too much of a brain receptor called N-methyl-D-aspartate (NMDA receptor for short). One Alzheimer’s treatment uses a drug called memantine to block these NMDA receptors. But memantine can’t tell the difference between the NMDA receptors we need to function and the extra ones that cause disease. It attacks them all. As a result, the side effects — like hallucinations and coma — are severe, and so memantine is mostly used for late-stage Alzheimer’s when the benefits outweigh the risks. Now, in a study published this month in Nano Letters, researchers led by Alex Savchenko at Stanford University and Elena Molokanova at the startup Nanotools Bioscience created a nanoparticle that only blocks the extra NMDA.
“This is the first time we’ve been able to target the receptors like this,” says Molokanova. “We hope that this can be brought to the clinic as fast as possible to be applied to Alzheimer’s and other diseases.”
“Good” and “bad” NMDA receptors are found in different parts of the brain. The “good” NMDA receptors are in the synapses, or the spaces between neurons, and accordingly called synaptic NMDA or sNMDA. The “bad” NMDA are everywhere else, and therefore called extrasynaptic NMDA, or eNMDA.
Two synapses communicating are like two people talking to each other, says Savchenko. All is well when they can hear themselves clearly in a quiet room. But if there is too much background noise — like when there’s all this extrasynaptic NMDA — the speakers get disoriented and can’t continue the conversation. In the worst-case scenario, too much eNMDA can kill the cell and lead to neurological degeneration.
The idea that too much NMDA is responsible for neurological disease has been around for decades, according to Howard Gendelman, a professor of pharmacology at the University of Nebraska Medical Center who was not involved with the study. “People have made a lot of money on trying to block it, but the clinical use hasn’t been that high because of the side effects,” he says, “so what they’re doing here is kind of cool and it might change things.”
Savchenko and Molokanova created a particle that combines gold, memantine, and polyethylene glycol, the active ingredient in antifreeze. Gold and polyethylene glycol are both popular choices for nanoparticles. Gold is nontoxic and stable, while polyethylene glycol also adds stability, according to Gendelman. The particle is called AuM — Au is the chemical symbol for gold — and measures 13 nanometers. (For context, 10 nanometers is how much the average beard hair grows in one second.) It’s too big to fit in the synapses between neurons, but still big enough to interact with the NMDA everywhere else.
To test AuM, Savchenko and Molokanova first used a technique called calcium imaging on brain cells. All neurons use calcium ions to transmit information through the synapses, so by recording how the amount of calcium changes “we can actually watch neurons talking to each other in real time,” says Savchenko. The scientists tested neurons with either AuM or memantine only. The memantine alone blocked the synaptic NMDA, just as predicted. AuM did not.
Calcium imaging records activity in a network of cells, but the researchers also wanted to see what happens in a single neuron. To do this, they used a method from electrophysiology. The scientists created a tiny and very precise glass pipette with an opening of one micron in diameter that holds an electrode. A second electrode stays outside the pipette. The pipette touches the neuron and partially sucks it in. The electrodes then create an electric current inside the pipette that the researchers recorded to see how the neuron was behaving. Same result: free memantine blocked the synaptic NMDA, but AuM did not. When NMDA receptors everywhere were activated, AuM only blocked some of them. This confirms that it does target the eNMDA, while leaving the sNMDA alone.
These results are promising, says Gendelman of the University of Nebraska Medical Center, though he cautions that it’s important not to overhype new developments because diseases like Alzheimer’s are so complex. “There are so many ‘causes’ for this disease, even shutting down one arm of this will not affect the eight other arms that are going on with the disease process,” he says. In addition, the field is so new that we don’t know the long-term effects of this, or any, nanomedicine therapy. For example, while gold is used in nanoparticles because it is non-toxic, we still don’t know what happens to someone with chronic illness who accumulates a lot of gold in their body over 15 years.
Molokanova and Savchenko acknowledge that there must be further studies. Still, they are excited by the possibilities of the particle, which they compare to putting a leash on a dog. “Before this, the dog — or memantine — would run wild,” says Savchenko. “Now the dog is more useful, in a sense, because you have a way to control where it goes.”