beta-Lactolin improves mitochondrial function in A beta-treated mouse hippocampal neuronal cell line and a human iPSC-derived neuronal cell model of Alzheimer's disease

Mitochondrial dysfunctions are a key hallmark of Alzheimer's disease (AD). beta-Lactolin, a whey-derived glycine-threonine-tryptophan-tyrosine tetrapeptide, has been previously reported to prevent AD-like pathologies in an AD mouse model via regulation of microglial functions. However, the direct effect of beta-lactolin on neuronal cells and neuronal mitochondrial functions remains unknown. Here, we investigated the effects of beta-lactolin on mitochondrial functions in amyloid beta (A beta)-treated mouse hippocampal neuronal HT22 cells and human induced-pluripotent cell (hiPSC)-derived AD model neurons. Adding beta-lactolin to A beta-treated HT22 cells increased both the oxygen consumption rate and cellular ATP concentrations, suggesting that beta-lactolin improves mitochondrial respiration and energy production. Using high content image analysis, we found that beta-lactolin improved mitochondrial fragmentation, membrane potential, and oxidative stress in A beta-treated cells, eventually preventing neuronal cell death. From a mechanistic perspective, we found that beta-lactolin increased gene expression of mitofusin-2, which contributes to mitochondrial fusion events. Finally, we showed that beta-lactolin improves both mitochondrial morphologies and membrane potentials in hiPSC-derived AD model neurons. Taken together, beta-lactolin improved mitochondrial functions AD-related neuronal cell models and prevented neuronal cell death. The dual function of beta-lactolin on both neuron and microglia marks an advantage in maintaining neuronal health.