Modeling Neurodegenerative Diseases with Induced Pluripotent Stem Cells

Advances in induced pluripotent stem cell (iPSC) technology have transformed the study of neurodegenerative diseases by enabling the generation of patient-specific neural cells that faithfully recapitulate human pathology. Somatic cells reprogrammed into iPSCs retain the donor’s genetic background, allowing direct comparison of disease and control phenotypes in neurons, astrocytes and microglia. Three-dimensional culture systems such as organoids and hydrogel matrices enhance cellular maturation and permit observation of hallmark features including amyloid-β aggregation, tau hyperphosphorylation and synaptic dysfunction in an age-dependent manner. Integration with genome editing techniques enables the creation of isogenic controls to dissect the contribution of single risk alleles. Microfluidic platforms further refine these models by controlling fluid flow, nutrient gradients and cell–cell interactions, thereby mimicking the brain’s microenvironment. Collectively, iPSC-based models offer a versatile toolbox for probing pathogenic mechanisms, identifying phenotypic biomarkers and conducting high-throughput drug screening. By bridging the gap between conventional two-dimensional cultures and animal models, these systems hold great promise for accelerating translational research and developing targeted therapies for Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and related disorders.

Research from Nature Portfolio

Recent studies have harnessed microfluidic chip platforms combined with patient-derived iPSCs to model multifactorial pathogenesis across different neurodegenerative diseases, demonstrating the ability of organoid-on-chip systems to reproduce neuronal connectivity, proteinopathy and neuroinflammatory responses under tightly controlled fluidic conditions. These devices enable parallel assessment of pathogenic cascades and facilitate screening of candidate therapeutics in an environment that closely resembles human physiology. In a complementary approach, cerebral organoids generated from iPSCs carrying the APOE ε4 risk allele have been shown to exhibit exacerbated synaptic loss, heightened amyloid-β and phosphorylated tau accumulation, and altered RNA metabolism; correction of the APOE4 genotype in isogenic lines attenuates these defects, providing key mechanistic insight into allele-specific pathways and paving the way for precision-medicine strategies.

Modeling Neurodegenerative Diseases with Induced Pluripotent Stem Cells publication trend

The graph below shows the total number of articles in modeling neurodegenerative diseases with induced pluripotent stem cells across all publications each year (not limited to Nature Index journals).

Technical terms

Induced pluripotent stem cell (iPSC): A somatic cell reprogrammed to a pluripotent state capable of differentiating into various specialised cell types.

Cerebral organoid: A three-dimensional assembly of neural cells derived from iPSCs that mimics aspects of human brain structure and development.

Microfluidic organoid-on-chip: A miniaturised platform integrating organoid cultures with microfluidic channels to control the tissue microenvironment and fluid dynamics.

Extracellular matrix (ECM): The complex network of proteins and polysaccharides surrounding cells that regulates cell adhesion, migration and signalling.

References

1. hiPSC-based models to decipher the contribution of human astrocytes to Alzheimer’s disease and potential therapeutics. Molecular Neurodegeneration (2023).
2. Neuropathogenesis-on-chips for neurodegenerative diseases. Nature Communications (2024).
3. The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models. Advanced Science (2023).
4. Aging phenotype in AD brain organoids: Track to success and challenges. Ageing Research Reviews (2024).
5. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nature Communications (2020).