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 is largely unknown. Recent research published in journals Biomedicine and pharmacotherapy The researchers found that lithium chloride alters multiple cellular pathways beyond its primary targets, altering the activity of various enzymes and structural proteins associated with dementia. These results suggest that changing the type of lithium used in treatment may improve outcomes for patients experiencing memory loss and cognitive decline.
Alzheimer’s disease is the most common form of dementia and is characterized by two major physical features of 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 typically helps stabilize the internal structure of brain cells. In people with dementia, tau undergoes a chemical change called hyperphosphorylation.
Phosphorylation is a normal chemical reaction in which enzymes called kinases attach small chemical tags known as phosphate groups to proteins. These tags act like switches, turning the protein’s function on or off. When hyperphosphorylation occurs, the kinase attaches an excess of phosphate groups to the tau protein. This causes the proteins to detach from the cell’s structural support and become entangled, ultimately damaging the nerve cell.
One particular kinase, called GSK-3β, is highly overactive in the brains of Alzheimer’s patients. This excessive activity is believed to be the main cause of abnormal protein tangles that disrupt cognitive function. Medical researchers have spent years researching drugs that block this enzyme to stop the tau protein from untangling. Lithium chloride is a compound that strongly inhibits this particular kinase.
Although experiments using this compound were successful in reducing tau phosphorylation, clinical trials testing lithium in human patients have yielded inconsistent results. Another research paper recently provided a possible explanation for these mixed medical outcomes. Researchers found that amyloid beta plaques can trap inorganic lithium salts. This means that the drug is absorbed by the plaque before it can reach its target kinase within the cell. Using different types of organolithium salts that avoid these plaques may solve the problem.
Before moving forward with new clinical trials, scientists needed a better map of exactly what lithium chloride does inside cells. Dorit Hofmann, a project researcher at the University of Eastern Finland, led a research team to uncover these cellular mechanisms. Virupi Ahola, research manager at the institute, co-authored the study with a team of biologists and bioinformatics experts. The research group aimed to map how lithium chloride interacts with tau, kinases, and other biological pathways.
“Our study identified several novel Alzheimer’s disease-related phosphorylation sites affected by lithium chloride treatment and predicted changes in the activity of multiple kinases and Rho GTPases,” Hoffman and Ahola said in a university press release. “The role of these molecules in Alzheimer’s disease requires further research to better understand the effects of lithium compounds on Alzheimer’s disease pathology and disease mechanisms.”
The researchers used two different laboratory models to observe how lithium chloride affected cells. First, they used co-culture, a method in which two types of cells are grown together in a dish. They combined mouse nerve cells with mouse microglia, the brain’s primary immune cells. The team then applied lipopolysaccharide and interferon gamma, compounds that cause a severe inflammatory response in immune cells.
Through this simulated brain inflammation, we succeeded in hyperphosphorylating tau protein within neurons. 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 inflammation.
The research team observed that lithium treatment reduced tau phosphorylation at specific binding sites. The highest concentrations of lithium returned chemical tags at specific sites on the tau protein to normal levels. At another binding site, low concentrations of lithium actually increased the number of phosphate tags. This shows that the drug’s effectiveness is highly dependent on the dose and the specific part of the protein being tested.
In the second experiment, the scientists used a line of human bone cancer cells. These cells are genetically modified to produce large amounts of mutated human tau protein. This particular genetic mutation mimics the extreme hyperphosphorylation seen in neurodegenerative diseases. The researchers treated these cells with very high doses of lithium chloride and examined them using phosphoproteomics.
Phosphoproteomics is an advanced analytical technique that allows scientists to observe thousands of phosphorylated proteins throughout a cell at once. Rather than just checking one or two proteins, researchers can plan a comprehensive snapshot of cellular activity. In this human cell model, the researchers observed a significant reduction in tau phosphorylation. Lithium treatment successfully removed phosphate groups from multiple sites on the tau protein, including several binding sites closely associated with the pathology of Alzheimer’s disease.
Extensive data from phosphoproteomic analyzes also revealed that lithium chloride does not only block the targeted GSK-3β enzyme. The compound reduced the activity of several other kinases, including one called PKCα, which has previously been associated with cognitive decline. At the same time, the treatment appeared to increase the activity of several other kinases. This indicates that lithium has widespread effects on cellular 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 that control the shape and movement of the cell’s internal skeleton, known as the actin cytoskeleton. Mammals have 20 different variations of these signaling proteins that must be constantly turned on and off to maintain healthy cell structure. Data show changes in phosphorylation of several proteins that control these switches, indicating dysregulation of this structural pathway.
Although this data provides detailed cytochemistry, there are several caveats to this study. The high concentrations of lithium chloride used in human cell models are far above what the human body can safely tolerate. The therapeutic range of lithium is very narrow, meaning that the amount needed to treat disease is very close to the amount that causes severe toxicity. Taking such high doses in clinical practice can pose significant risks to the patient’s kidneys and thyroid.
Future studies should investigate how lower, safer doses of lithium affect these newly identified kinases and structural proteins. Scientists also need to determine whether reduced activity of certain Rho GTPases helps or harms brain cells during the progression of dementia. Mapping these pathways at different doses can help drug 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 cellular models,” was authored by Dorit Hoffmann, Virpi Ahola, Nadine Huber, Teemu Natunen, Stina Leskelä, MariTakalo, Henna Martiskainen, Stephanie Ballweg, Egor Vorontsov, Stefan Selzer, Pekka Kallio, and Ian Pike. Jouni Silvio, Annakaisa Haapasaro, Mikko Hiltunen.
