Human Stem Cell-Derived Models of the Alzheimer’s Disease Neuroimmune System

Mounting evidence implicates dysregulation of the neuroimmune system in Alzheimer’s disease (AD). Neuroimmune cells, namely microglia and astrocytes, have the potential to contribute to AD through mechanisms such as promoting neuroinflammation and propagating amyloid-β (Aβ) and tau aggregates. Human induced pluripotent stem cell (hiPSC)-derived models offer advantages for studying the AD neuroimmune system, such as recapitulating genetic variants associated with the disease and allowing for precise manipulation of human cells in vitro. Here, we provide an overview of modern techniques for generating 2-dimensional (2D) monocultures and co-cultures, 3-dimensional (3D) organoids and assembloids, and chimeras containing hiPSC-derived microglia and astrocytes. Then, we highlight recent studies that have utilized hiPSC-derived neuroimmune models to investigate AD risk variants in genes encoding apolipoprotein E (APOE) and triggering receptor on myeloid cells 2 (TREM2), mutations known to cause familial AD in genes encoding presenilin 1 (PSEN1) and 2 (PSEN2) and amyloid precursor protein (APP), and trisomy 21 leading to Down syndrome-associated AD (DS-AD). We then briefly summarize recent studies that have utilized hiPSC-derived neuroimmune models lacking disease-associated variants to study the clearance of Aβ and tau aggregates. Finally, we discuss notable limitations of these models and reflect on future directions for this area of research, including the use of cultures with increasing cellular diversity and structural complexity, advancements in live-imaging techniques for detecting AD pathology in vitro, and drug screening.