3D immuno-glial-neurovascular human brain platform for high-fidelity disease modelling

17 October 2025

Neurodegenerative disorders, such as Alzheimer’s disease (AD), are highly debilitating, progressive disorders that affect cognitive function and behaviour. Traditionally, biomedical research into AD has relied on animals to model AD pathophysiology and develop treatments. However, none of the treatments tested in AD animal models were able to halt or reverse cognitive decline in AD patients. The failure rate in clinical trials of drugs developed and validated in animal models of AD is as high as 99.6%.

This disappointing result is in large part due to major inter-species differences in brain structure, function, behaviour, aging mechanisms, genetics, and gene expression regulation, which preclude faithful recapitulation in animals of this uniquely human disorder.

To advance human-based cell models that faithfully recapitulate human-specific brain physiology and patient-specific pathophysiology, Alice Stanton et al. at Massachusetts Institute of Technology have developed a human iPSC-derived preclinical brain model composed of 3D immuno-glial-neurovascular units. 

Termed miBrains, short for multicellular integrated brains, this novel human brain tissue platform has the particularity of integrating six major brain cell types of the forebrain/cortex - pericytes, astrocytes, endothelial cells, neurons, oligodendroglia, and microglia. As such, it is particularly suited for studying neurological diseases involving neuroinflammation, blood-brain barrier dysfunction, glial pathology, and myelination.

To enhance neuronal activity and support cellular assembly, the researchers have engineered an innovative, tunable and biochemically defined extracellular matrix (ECM)-mimicking scaffolding, Neuromatrix Hydrogel, that incorporates brain ECM proteins and the basement membrane peptide-mimic arginylglycylaspartic acid. Obtained miBrains recapitulate in vivo–like hallmarks of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. The presence of the key cell types enables to dissect the role of each cell type, isolate the inter-cellular interactions that drive pathogenesis, and develop novel therapies that target these drivers.

Studies in AD patient populations have indicated that the APOE ε4 isoform of the APOE gene is a common variant strongly associated with familial late-onset AD and sporadic AD. miBrains integrate independently differentiated cell types, enabling to decouple cell type-specific phenotypes from genotypes and investigate the effects of genetic variants in specific cell types, in this particular study of APOE4 and APOE3 variants in astrocytes.

The impact of the APOE gene can vary between patients, likely due to inter-individual differences in genomic region containing the APOE gene and in regulation of expression of AD-associated genes. Donor-specific, hiPSC-derived cells are ideally suited for capturing this heterogeneity across patient populations and probing the functional consequences of mutations, paving the way for personalized medicine.

Astrocytes are one of the key players in AD, since they help clear the Aβ plaques, provide mechanical support to neurons, modulate glucose metabolism, and participate in signaling to endothelial cells, and their dysfunction in AD contributes to neuroinflammation, Aβ accumulation, impaired energy supply, vascular integrity, and neuronal loss.  

To unveil the mechanisms by which astrocytes carrying the APOE4 variant drive AD pathology, the researchers have conducted experiments in which the phenotype of miBrains containing APOE4 for astrocytes and APOE3 for all other cell types were compared to those of all-APOE3 miBrains and all-APOE4 miBrains.

APOE3 miBrains containing APOE4 astrocytes still exhibited Aβ and tau accumulation, demonstrating that APOE4 astrocytes are sufficient to induce AD-like pathology, possibly through non-cell-autonomous effects fuelled by impaired Aβ clearance, inflammatory signaling, and metabolic dysfunction in APOE4 astrocytes.

In comparison to APOE4 miBrains dosed with media from cultures of astrocytes or microglia alone, APOE4 miBrains dosed with culture media from astrocytes and microglia combined showed increase in phosphorylated tau, pointing to the existence of distinct secreted factors generated through a cross-talk between microglia and astrocytes.

As to further enhance the biomimicry of this platform for preclinical research, the future projects will include the use of microfluidic devices to simulate blood flow circulation within the miBrain.

What Puts It on the Frontier

• Engineering of a 3D brain tissue model containing six major cell types of the forebrain/cortex - pericytes, astrocytes, endothelial cells, neurons, oligodendroglia, and microglia

• Engineering of an innovative ECM-mimicking scaffolding that enhances neuronal activity

• Integration of independently differentiated cell types, enabling to decouple cell type-specific phenotypes from genotypes

• Use of patient-specific, hiPSC-derived cells that capture inter-individual differences in genetics

Impact Snapshot

• Enhanced physiological relevance of in vitro models of human neurodegenerative disorders

• Human-relevant insights into the cross-talk between key brain cell types

• Elucidation of the genetic, molecular and cellular mechanisms responsible for Alzheimer's

• Development of targeted therapies for heterogenous disease subtypes. Personalized medicine

Reference

Stanton AE, Bubnys A, Agbas E, James B, Park DS, Jiang A, Pinals RL, Liu L, Truong N, Loon A, et al. Engineered 3D immuno-glial-neurovascular human miBrain model. Proceedings of the National Academy of Sciences. Oct. 2025; 122(42):e2511596122. https://doi.org/10.1073/pnas.2511596122.