Alzheimer's disease and synapse Loss: What can we learn from induced pluripotent stem Cells? hiPSCs and Alzheimer's Disease Modeling

Background: Synaptic dysfunction is a major contributor to Alzheimeŕ's disease (AD) pathogenesis in addition to the formation of neuritic β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau protein. However, how these features contribute to synaptic dysfunction and axonal loss remains unclear. While years of considerable effort have been devoted to gaining an improved understanding of this devastating disease, the unavailability of patient-derived tissues, considerable genetic heterogeneity, and lack of animal models that faithfully recapitulate human AD have hampered the development of effective treatment options. Ongoing progress in human induced pluripotent stem cell (hiPSC) technology has permitted the derivation of patient- and disease-specific stem cells with unlimited self-renewal capacity. These cells can differentiate into AD-affected cell types, which support studies of disease mechanisms, drug discovery, and the development of cell replacement therapies in traditional and advanced cell culture models. Aim of Review: To summarize current hiPSC-based AD models, highlighting the associated achievements and challenges with a primary focus on neuron and synapse loss. Key Scientific Concepts of Review: We aim to identify how hiPSC models can contribute to understanding AD-associated synaptic dysfunction and axonal loss. hiPSC-derived neural cells, astrocytes, and microglia, as well as more sophisticated cellular organoids, may represent reliable models to investigate AD and identify early markers of AD-associated neural degeneration.