Validation of Mitochondria‐Targeted AD Therapeutics in Human Neuronal Cells

Neurons and astrocytes were differentiated separately from human induced pluripotent stem cells (HiPSC) derived from Late‐Onset Alzheimer Disease (LOAD) female patients carrying Apolipoprotein E4 (ApoE4) allele. Cells from age and sex matched healthy subject carrying Apolipoprotein E3 allele were used as control. These neuronal, astrocytic, and their co‐cultures were assessed to investigate cell‐specific AD phenotypes (Figure 1). We recently demonstrated that application of a small molecule partial mitochondrial complex I inhibitor CP2 blocked neurodegeneration and cognitive decline in multiple mouse models of AD. However, the demonstration that this novel therapeutic approach is efficacious in human brain cells has not been done. Here, we aimed to validate neuroprotective mechanisms induced by CP2 using patient‐derived neuronal cells form LOAD patient. Outcomes will further support the development of these compounds for clinical application.