Abstract
Alzheimer's disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype, and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe(²⁺), increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation, and excessive ROS production. Moreover, lithium normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca(²⁺) channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses, and inhibition of disrupted Ca(2+) signaling. Given its demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.