Cellular bioenergetics in human iPSC–derived glutamatergic neurons in health and disease

Abstract Neurodegenerative diseases (NDs) are chronic, progressive disorders that present with severe cognitive decline affecting the aging population. Fundamental investigations have identified key pathological processes including abnormal protein aggregation, neurotransmitter imbalances, and overall bioenergetic dysfunction. Intriguingly, the glutamatergic neurotransmitter system in the cerebral cortex appears to be particularly affected in NDs, and disturbances in its circuits have been associated with memory impairments. To date, no treatment is available to prevent disease progression. Efforts to develop successful therapeutics may benefit from disease-relevant models that enable the study of early pathology stages. Models based on human-induced pluripotent stem cells (hiPSCs) hold great promise as approaches to unravel mechanistic insights in specific neuronal populations affected in NDs. Here we revisit the current approaches differentiating hiPSCs into cortical glutamatergic neurons in order to assess neuronal hypometabolism, one of the most prevalent early phenotype in NDs, followed by an overview of studies evaluating brain energy metabolism in hiPSC-derived (glutamatergic) neurons from ND patients.