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

A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer’s disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer’s disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue. Klimmt, Cardoso Gonçalves et al. developed a reproducible human three-dimensional brain tissue model with neurons, astrocytes and microglia, replicating in-vivo-like maturation and enabling the study of Alzheimer’s disease-relevant perturbations and drug responses.

Modeling Alzheimer’s disease with brain organoids: mechanisms, applications, and future directions

Key findings demonstrate that organoids effectively capture genotype–phenotype relationships for major AD genes, enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms.

iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy.

Neuroinflammation in Alzheimer’s and Parkinson’s diseases: pathogenic mechanisms and therapeutic strategies

It is illustrated how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration.

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer’s disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell–cell interaction analyses prioritize APOE–SORL1 and APOE–TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery. Molecular profiling of myeloid cells from the prefrontal cortex of 1,607 donors with varying degrees of Alzheimer’s disease neuropathology delineates distinct myeloid subtypes and identifies changes associated with aging and disease progression.

Characterization and pharmacological modulation of Alzheimer’s disease-associated human microglial states

Microglia are central mediators of Alzheimer’s disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired Aβ phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.