Human-Induced Pluripotent Stem Cell-Based Models for Studying Sex-Specific Differences in Neurodegenerative Diseases

The prevalence of neurodegenerative diseases is steadily increasing worldwide, and epidemiological studies strongly suggest that many of the diseases are sex-biased. It has long been suggested that biological sex differences are crucial for neurodegenerative diseases; however, how biological sex affects disease initiation, progression, and severity is not well-understood. Sex is a critical biological variable that should be taken into account in basic research, and this review aims to highlight the utility of human-induced pluripotent stem cells (iPSC)-derived models for studying sex-specific differences in neurodegenerative diseases, with advantages and limitations. In vitro systems utilizing species-specific, renewable, and physiologically relevant cell sources can provide powerful platforms for mechanistic studies, toxicity testings, and drug discovery. Matched healthy, patient-derived, and gene-corrected human iPSCs, from both sexes, can be utilized to generate neuronal and glial cell types affected by specific neurodegenerative diseases to study sex-specific differences in two-dimensional (2D) and three-dimensional (3D) human culture systems. Such relatively simple and well-controlled systems can significantly contribute to the elucidation of molecular mechanisms underlying sex-specific differences, which can yield effective, and potentially sex-based strategies, against neurodegenerative diseases.