Lithium salts have shown promise in treating Alzheimer’s disease by preventing certain proteins in the brain from clumping together, but how they affect cells on a broader scale remains largely unexplored. A recent study published in the journal Biomedicine & Pharmacotherapy reveals that lithium chloride alters multiple cellular pathways beyond its primary target, changing the activity of various enzymes and structural proteins linked to dementia. These results suggest that modifying the type of lithium used in medical treatments could improve outcomes for patients experiencing memory loss and cognitive decline.
Alzheimer’s disease is the most common form of dementia, characterized by two main physical features in the brain. The first is the buildup of amyloid-beta, a protein that forms sticky plaques between nerve cells. The second involves a protein called Tau, which normally helps stabilize the internal structure of brain cells. In people with dementia, Tau undergoes a chemical alteration called hyperphosphorylation.
Phosphorylation is a normal chemical reaction where enzymes called kinases attach small chemical tags, known as phosphate groups, to a protein. These tags act like switches, turning the protein’s functions on or off. When hyperphosphorylation occurs, kinases attach too many phosphate groups to the Tau protein. This causes the protein to detach from the cell’s structural supports and tangle together, which ultimately damages the nerve cell.
One specific kinase, called GSK-3β, is highly overactive in the brains of people with Alzheimer’s disease. This overactivity is considered a major driver of the abnormal protein tangling that destroys cognitive function. Medical researchers have spent years testing drugs that block this enzyme to stop the Tau protein from tangling. Lithium chloride is a chemical compound that strongly inhibits this specific kinase.
Laboratory experiments using this compound have successfully reduced Tau phosphorylation, but clinical trials testing lithium on human patients have yielded inconsistent results. A separate research paper recently offered a possible explanation for these mixed medical outcomes. Researchers found that amyloid-beta plaques can trap inorganic lithium salts, meaning the drug gets absorbed by the plaques before it can reach the targeted kinases inside the cells. Using different types of organic lithium salts that avoid these plaques might solve the problem.
Before advancing to new clinical trials, scientists needed a better map of exactly what lithium chloride does inside a cell. Dorit Hoffmann, a project researcher at the University of Eastern Finland, led a team of investigators to uncover these cellular mechanisms. Virpi Ahola, a research manager at the same institution, co-authored the study alongside a team of biologists and bioinformatics specialists. The research group aimed to map how lithium chloride interacts with Tau, kinases, and other biological pathways.
“Our study identified several novel AD-relevant phosphosites affected by lithium chloride treatment and predicts alterations in the activity of multiple kinases and Rho GTPases,” Hoffmann and Ahola noted in a university press release. “The role of these molecules in AD requires further investigation to better understand the impact of lithium compounds on AD pathology and disease mechanisms.”
The researchers used two different laboratory models to observe how lithium chloride affects cells. First, they used a co-culture, which is a method of growing two types of cells together in a dish. They combined mouse nerve cells with mouse microglia, which are the primary immune cells of the brain. The team then applied lipopolysaccharide and interferon gamma, which are compounds that trigger a severe inflammatory response in the immune cells.
This simulated brain inflammation successfully caused the Tau proteins in the nerve cells to become hyperphosphorylated. Once the disease model was established, the researchers treated the cells with varying concentrations of lithium chloride. They tracked the results using a technique that detects specific proteins and their phosphate tags. They wanted to see if the drug could reverse the damage caused by the inflammation.
The team observed that the lithium treatment reduced Tau phosphorylation at certain attachment sites. The highest concentration of lithium returned the chemical tags to normal levels at one specific site on the Tau protein. At another attachment site, low concentrations of lithium actually increased the number of phosphate tags. This indicates that the drug’s effects depend heavily on the dosage and the specific part of the protein being examined.
In their second experiment, the scientists used a line of human bone cancer cells. These cells were genetically modified to produce large amounts of a mutated human Tau protein. The specific genetic mutation mimics the extreme hyperphosphorylation seen in neurodegenerative diseases. The research team treated these cells with a very high dose of lithium chloride and examined them using phosphoproteomics.
Phosphoproteomics is an advanced analytical technique that allows scientists to look at thousands of phosphorylated proteins across the entire cell at once. Instead of just checking one or two proteins, researchers can map out a comprehensive snapshot of cellular activity. In this human cell model, the researchers observed a broad reduction in Tau phosphorylation. The lithium treatment successfully removed phosphate groups from multiple sites on the Tau protein, including several attachment sites closely associated with Alzheimer’s disease pathology.
The broad data from the phosphoproteomics analysis also revealed that lithium chloride does not just block the targeted GSK-3β enzyme. The compound reduced the activity of several other kinases, including one called PKCα, which has previously been linked to cognitive decline. At the same time, the treatment seemed to increase the activity of a few other kinases. This shows that lithium exerts a broad influence over a cell’s regulatory enzymes.
Additionally, the researchers observed changes in a biological network known as the Rho GTPase signaling pathway. Rho GTPases are proteins that act as molecular switches to control the shape and movement of the cell’s internal skeleton, known as the actin cytoskeleton. Mammals have twenty different variations of these signaling proteins, which must constantly be turned on and off to maintain a healthy cell structure. The data showed altered phosphorylation in several proteins that regulate these switches, indicating dysregulation in this structural pathway.
While the data provide a detailed look at cellular chemistry, the study comes with a few caveats. The high concentrations of lithium chloride used in the human cell model are much higher than what a human body can safely tolerate. Lithium has a very narrow therapeutic window, meaning the amount needed to treat a disease is very close to the amount that causes severe toxicity. A dose this high in a clinical setting would pose severe risks to a patient’s kidneys and thyroid gland.
Future research will need to explore how lower, safer doses of lithium affect these newly identified kinases and structural proteins. Scientists must also clarify whether decreasing the activity of certain Rho GTPases helps or harms brain cells during the progression of dementia. Mapping these pathways at varying dosages will help pharmaceutical developers design safer treatments. By identifying which specific enzymes to target, researchers hope to find lithium compounds that can treat memory loss without causing dangerous side effects.
The study, “Lithium chloride alters Tau phosphorylation, kinase activity, and Rho GTPase signaling in cell models,” was authored by Dorit Hoffmann, Virpi Ahola, Nadine Huber, Teemu Natunen, Stina Leskelä, Mari Takalo, Henna Martiskainen, Stephanie Ballweg, Egor Vorontsov, Stefan Selzer, Pekka Kallio, Ian Pike, Jouni Sirviö, Annakaisa Haapasalo, and Mikko Hiltunen.
