Grad Student UCSD San Diego, California, United States
Abstract: Aging is the primary risk factor for neurodegenerative diseases such as Alzheimer’s Disease (AD), which exclusively affects the elderly. Despite its critical role, our understanding of the intersection between aging and neurodegeneration remains incomplete due to the limitations of existing models: postmortem studies do not allow for mechanistic studies, and animal models fall short in capturing the interplay of human biological aging and genetics. While iPSC-derived models provide valuable patient-specific insights, they are rejuvenated cells that lack the physiological aging signatures, and represent fetal brain characteristics instead. To address these gaps, a more authentic 3D model that integrates human aging-related molecular disease mechanisms with pathological AD signatures in a patient-specific manner is desirable. Here, we harness the potential of induced neurons (iNs), directly reprogrammed from patient fibroblasts, which uniquely retain critical aging signatures, exhibit adult 3R/4R Tau splicing, and replicate aging-associated AD phenotypes. However, traditional 2D iN cultures lack the 3D complexity and dynamic interactions—such as cell-extracellular matrix signaling—essential for replicating the aging human brain's microenvironment and extracellular AD pathology. Here, we developed a 3D iN construct system that integrates iNs with synthetic microcarriers. These microcarriers are engineered to support complex neuronal networks, promote synaptic connectivity, and sustain long-term cell viability in a physiologically relevant 3D environment. Notably, our system successfully models the endogenous production of extracellular matrix proteins, including the buildup of toxic protein (such as beta amyloid) in cultures derived from control, sporadic AD, and familial AD patients. This demonstrates the potential of our platform to uncover key mechanisms underlying aging and neurodegeneration. By combining the aging signatures of iNs with the architectural sophistication of 3D biomaterials, this model offers a transformative approach to studying age-related mechanisms in AD. Furthermore, it provides a robust platform for therapeutic discovery, enabling the identification of interventions that reduce pathological burden and promote neuronal resilience
