Lithium chloride may affect many cellular level changes in Alzheimer’s disease, a new study from the University of Eastern Finland (UEF) shows.

Alzheimer's disease (AD) is the most common form of dementia. A central pathological feature of AD is the hyperphosphorylation and intracellular aggregation of Tau in addition to the accumulation of β-amyloid (Aβ)-containing plaques in the brain.

Lithium salts, in particular lithium chloride and lithium carbonate, have been used in cell and animal models of AD to reduce the hyperphosphorylation and subsequent aggregation of Tau. On the other hand, clinical studies have shown mixed results with sometimes little or no cognitive improvement.

A recent US study offered an explanation for this discrepancy: Inorganic lithium salts, such as lithium chloride and lithium carbonate, can be sequestered in Aβ plaques, reducing their bioavailability. Using organic lithium salts, which can evade sequestration, could improve clinical outcomes in future trials, making lithium salts an attractive therapeutic approach.

“This may lead to renewed interest in lithium salts for the prevention and treatment of AD and also underlines the importance of basic research to increase our understanding of disease mechanisms and interactions of drugs used in clinical trials”, says Project Researcher Dorit Hoffmann of the A. I. Virtanen Institute for Molecular Sciences at the University of Eastern Finland.

To expand our knowledge on the effects of lithium on AD-relevant pathology and pathways, Hoffmann and colleagues used two cell-based models of Tau hyperphosphorylation and assessed the effect of lithium chloride using different proteomic approaches.

As expected, the treatment reduced phosphorylation of Tau at known phosphosites, but the analyses also revealed several new AD-relevant Tau phosphosites affected by the treatment.

The serine/threonine kinase GSK-3β is overactive in AD and considered to be the major kinase responsible for the abnormal phosphorylation of Tau. Interestingly, the present study suggests that lithium chloride may affect other kinases as well. The study also revealed that treatment with lithium chloride may lead to significant changes in the Rho GTPase signaling pathway. While increased activity in some Rho GTPases is known to be involved in the pathogenesis of AD in several ways, the role of others is not yet well understood.

“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. The role of these molecules in AD requires further investigation to better understand the impact of lithium compounds on AD pathology and disease mechanisms,” Hoffmann and Research Manager Virpi Ahola from UEF Bioinformatics Center summarise.

Professors Mikko Hiltunen and Annakaisa Haapasalo also agree: “The findings so far indicate that the effects of different lithium salts remain insufficiently understood. More detailed analyses could reveal compounds better suitable for future clinical trials.”

The study was part of research projects funded by the Research Council of Finland, Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, and the strategic Neuroscience funding of the University of Eastern Finland.