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

Brain Organoids in Alzheimer’s and Parkinson’s Disease: Clinical Applications and Translational Perspectives

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

An overview of modern techniques for generating 2-dimensional monocultures and co-cultures, 3-dimensional organoids and assembloids, and chimeras containing hiPSC-derived microglia and astrocytes is provided.

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.

Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point.

Human brain organoids have evolved from early neurodevelopmental models into platforms for therapeutic discovery. Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose-and ensuring reproducibility, scalability, and accessibility-will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.

Brain Organoids as Emerging Platforms for Modeling CNS Infections: Neuropathogenesis, Therapeutic Discovery, and Drug Delivery.

Neurotropic viruses remain a persistent global health challenge, and the mechanisms by which they damage the human brain are not yet fully understood. Animal models are often limited by human-specific aspects of CNS biology, whereas two-dimensional (2D) cell cultures cannot recapitulate the complex three-dimensional (3D) cellular interactions that occur during viral infection of the brain. Over the past decade, brain organoids derived from human stem cells have emerged as physiologically relevant models that address these limitations. These 3D cultures self-assemble into structures containing neurons, astrocytes, and progenitor cells arranged in patterns that resemble early brain development. This review examines the application of brain organoids to the study of infections caused by Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), herpes simplex virus (HSV), and human immunodeficiency virus type 1 (HIV-1). Studies were screened from PubMed and shortlisted based on their relevance to organoid-based CNS infection modeling, antiviral drug screening, CNS-targeted drug delivery, and neuroinflammation. Organoid-based antiviral screening has identified promising compounds from libraries containing more than 1,000 candidates. Drug delivery strategies are also discussed, with particular emphasis on nanoparticles, polymer-based carriers, and extracellular vesicles (EVs) evaluated in organoid and spheroid models for their ability to cross the blood-brain barrier (BBB) and deliver therapeutic cargo to neural cells. The roles of damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs) in neuroinflammation, complement evasion, and chronic post-infection damage, including long COVID, are also examined. Current limitations, including the lack of functional vasculature, incomplete BBB components, and reproducibility challenges, are discussed. Despite these limitations, CNS organoids bridge the gap between basic research and clinical application, advancing the development of effective therapies for viral infections of the brain.

Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.

Parkinson's disease (PD) poses a major unmet therapeutic challenge, with most drug candidates failing in clinical translation despite promising animal model data. Human induced pluripotent stem cell-derived midbrain organoids recapitulate key PD pathological hallmarks - including dopaminergic neuron loss, α-synuclein aggregation, and neuroinflammation - in a genetically defined, human-specific context. This review summarizes drug screening studies in midbrain organoids across genetic, toxin-based, and α-synuclein preformed fibril models. We highlight therapeutic interventions that rescue PD phenotypes, compare organoid and animal model systems, and discuss the personalized medicine potential of patient-derived organoids. We also critically assess current limitations and outline how artificial intelligence integration and assembloid platforms are advancing organoid-based drug discovery towards regulatory acceptance.