Experimental Lithium Nasal Spray Using Gold Nanoparticles Improves Memory In Alzheimer’s-Model Mice

‘Trojan Horse’ Method Shows Potential For Fighting Brain Diseases And Infections

ROME — Lithium has been used to treat serious mood swings and bipolar disorder for more than a century, but it comes with a dangerous catch. The amount that helps is dangerously close to the amount that can poison the kidneys and thyroid. Patients taking lithium pills need regular blood tests to make sure their levels haven’t crept into the danger zone, a delicate balancing act that doesn’t always work.

Now, researchers in Italy have found a potential way around this problem, at least in mice. They’ve created tiny gold particles, smaller than most viruses, that carry lithium through the nose to the brain in mice. It’s like a molecular Trojan horse that sneaks past the body’s usual defenses and drops its cargo exactly where it’s needed.

The approach could eventually help with more than just mood disorders. The same brain enzyme that lithium targets also plays a role in Alzheimer’s disease, Parkinson’s disease, and even some viral brain infections. But these findings are still early: so far, the nasal spray has only been tested in laboratory mice.

Getting Lithium Where It Needs to Go

The research team, working at universities in Salerno and Rome, built their delivery system around gold nanoparticles, specks so small that 50,000 of them lined up would barely span the width of a human hair. Each particle is coated with glutathione, a molecule the body already makes as an antioxidant, and decorated with lithium ions stuck to the surface.

When mice received the spray through their nostrils, something remarkable happened. The particles traveled along nerve pathways from the nose into the brain, largely bypassing the bloodstream, with plasma lithium staying low. Blood tests confirmed this: even after five months of treatment, lithium levels stayed near baseline for untreated mice.

But in the hippocampus, the memory center of the brain, it was a different story. The particles successfully delivered their lithium payload and quieted down an overactive enzyme called GSK-3β. Think of this enzyme as a molecular switch that, when stuck in the “on” position, contributes to several brain diseases.

The secret to how these particles work lies in basic chemistry. The researchers propose that once inside brain cells, the particles encounter a soup of sodium and potassium ions, charged particles that are much more common than lithium. These ions essentially bump the lithium off its perch on the gold particles, releasing it exactly where it can do its job.

Much More Efficient Than Pills

In test tubes with human cells (SH-SY5Y cells; 24-hour exposure), the gold particles delivered lithium far more efficiently than simply adding lithium to the culture medium. Cells treated with the particles soaked up more than 26 times as much lithium compared to cells exposed to regular lithium chloride, even when the starting concentration outside the cells was identical.

Even at doses that would be completely ineffective if taken as a pill, the nanoparticles managed to dial down GSK-3β activity in the cells.

Reversing Memory Loss in Alzheimer’s Mice

The real test came with mice bred to develop Alzheimer’s-like symptoms. By 12 months old, roughly equivalent to a person in their 60s or 70s, these mice had serious memory problems.

The researchers divided them into two groups. One got plain water through their noses; the other got the lithium nanoparticles. The treatment schedule was intermittent: five days on, then 10 days off, repeated for two months.

Before treatment, both groups performed miserably on memory tests. In one test, mice were shown two objects, then later presented with one familiar object and one new one. Healthy mice naturally spend more time investigating the novel object because they remember the old one. The Alzheimer’s mice barely showed a preference, suggesting they didn’t remember which object they’d seen before. Their scores hovered around 45-49%, barely better than a coin flip.

After two months of nanoparticle treatment, the treated mice jumped to 66% on this recognition test. The untreated mice showed no improvement at all.

A similar pattern emerged in a maze test of spatial memory. Treated mice improved from getting the correct path about half the time to getting it right 68% of the time. Again, untreated mice stayed stuck at chance levels.

When the researchers examined brain tissue afterward, they found changes consistent with GSK-3β inhibition. The mice had less tau protein, the stuff that tangles up in Alzheimer’s disease, in their hippocampus. Total tau levels dropped by nearly half.

Safe for Months of Use

Safety was a major concern. Gold building up in the brain could trigger inflammation or other problems. But mice treated for five months showed no signs of trouble. Their weight stayed normal, their fur remained healthy, and they didn’t develop strange behaviors.

Gold did accumulate slightly in the brain over five months of treatment, but only to about three times background levels, a modest increase. More importantly, the researchers found gold showing up in the kidneys too, suggesting renal clearance may play a role in eliminating the particles from the body.

The key safety win was the blood lithium level. Even after five months, it stayed around 0.08 to 0.14 millimoles per liter, the normal range. Compare that to psychiatric patients taking lithium pills, who need to maintain levels between 0.8 and 1.2, with anything above 1.5 considered dangerous. Traditional lithium therapy means regular blood draws and constant vigilance for signs of toxicity.

Why This Enzyme Matters for Multiple Diseases

GSK-3β doesn’t just affect mood. Over the past 20 years, researchers have discovered it plays important roles in several brain diseases.

In Alzheimer’s, this enzyme is a key kinase that phosphorylates tau protein, causing it to clump into the tangles that strangle brain cells. It also helps produce the amyloid plaques that are the other hallmark of the disease.

In Parkinson’s disease, GSK-3β affects alpha-synuclein, another protein that forms damaging clumps in the brain.

The enzyme even helps certain viruses infect brain cells and multiply. This includes herpes simplex virus type 1, which some researchers think may contribute to Alzheimer’s when it reaches the brain, and coronaviruses like the one that causes COVID-19. Some early pandemic studies noticed that psychiatric patients already taking lithium seemed to fare better with COVID infections, though those findings are still preliminary.

The problem is that using enough lithium to help these conditions would require doses higher than what’s considered safe for long-term use in mood disorders. That’s where targeted brain delivery could make a difference.

From Lab Bench to Potential Treatment

Making the nanoparticles doesn’t require exotic equipment or rare materials. The researchers mixed gold chloride with glutathione and lithium hydroxide in water and alcohol, then added a common reducing agent to turn the gold into tiny particles. The particles naturally form aggregates stabilized by electrostatic interaction with lithium cations. They can be dried into a powder and later mixed back into water when needed.

The team has already patented the technology, and these mouse experiments represent proof that the concept works. But many questions remain before this could help people.

The Alzheimer’s mice got treatment for two months and showed clear benefits. But Alzheimer’s in people develops over many years. Would longer treatment keep working, or would the benefits plateau? How often would someone need to use the spray? The researchers found that effects lasted at least 10 days after stopping treatment, which is why they spaced out the doses, but the optimal schedule for humans is anyone’s guess.

There’s also the question of which condition would benefit most. For bipolar disorder, it might be possible to achieve good results with lower, safer doses of regular lithium pills, making this elaborate nanoparticle approach unnecessary. But for Alzheimer’s, where lithium shows promise in studies but hasn’t caught on because of toxicity worries, targeted delivery could be transformative.

The same goes for brain infections where GSK-3β is involved, like herpes encephalitis. Being able to deliver lithium more directly to brain tissue might open up treatment possibilities that regular pills can’t offer.

The gold nanoparticle technology might also work for other metals or drugs that normally can’t get past the brain’s protective barrier. The principle is simple: coat a gold nanoparticle with a protective molecule, stick your drug of choice to the surface, and let cellular chemistry release it once it’s inside.

For now, this remains a promising proof of concept in mice. It shows that a drug first used in the 1870s can be given new life with 21st-century nanotechnology. Whether it will actually help people with Alzheimer’s or other brain diseases will require years of additional research, including safety studies and clinical trials in humans. But it offers a glimpse of how we might be able to deliver treatments to the brain more precisely, potentially helping patients who currently have few good options.

Disclaimer: This article is for general information and education. It describes early, preclinical findings in mice on an experimental lithium-nanoparticle nasal spray. The approach is not approved for use in people, and its safety and effectiveness in humans are unknown. Do not use lithium or any nasal formulation without a clinician’s guidance. Never start, stop, or change medication based on this article. Lithium has a narrow therapeutic window and can be dangerous if misused. If you have questions about treatment, talk with a qualified health professional. If you are experiencing a medical emergency, call your local emergency number.