The prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long‐term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk‐based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic‐like indicators of increased pathological β‐amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long‐term stability of the platform is suited to study chronic brain disease including neurodegeneration.

Three-dimensional (3D) in vitro cell and tissue culture models, particularly for the central nervous system, allow for the exploration of mechanisms of organ development, cellular interactions, and disease progression within defined environments. Here, we describe the development and characterization of human 3D tissue models that promote the differentiation and long-term survival of functional neural networks. This work builds upon previous work where primary rodent neurons were successfully grown in a similar 3D system. The model was adapted to human induced pluripotent stem cells, allowing for a more direct exploration of the human condition. These tissue cultures show diverse cell populations, including neurons and astroglial cells, interacting in 3D and exhibit spontaneous neural activity confirmed through electrophysiological recordings and calcium imaging over at least nine months. This approach allows for the direct integration of pluripotent stem cells into the 3D construct, bypassing early neural differentiation steps (embryoid bodies and neural rosettes). The streamlined process, in combination with the longevity of the cultures, provides a system that can be manipulated to support a variety of experimental applications, including the study of network development, maturation, plasticity, and/or degeneration. This tissue model was tested with stem cells derived from healthy individuals as well as Alzheimer’s and Parkinson’s disease patients. We observed similar growth and gene expression, which indicates the feasibility of generating patient-derived brain tissue models. These could be used to uncover early stage biomarkers of the disease state, in turn supporting earlier diagnosis and improving understanding of disease progression. With additional model development, this approach would have potential use for investigating drug targets in neurodegenerative diseases.

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.