Grant: Undergraduate Student Research Awards (USRA)

We established brain organoid cultures, which are 3D aggregates of stem cell-derived neurons, astrocytes, oligodendrocytes, and microglia that spontaneously distribute and functionally interact in a manner similar to that seen in the brain. We are one of only TWO groups in the world that can generate human brain organoids in which microglia develop innately (most protocols require they be cultured separately and then added to the organoid culture). Dysfunction of microglia, the brain's immune cells, contributes to brain pathology. Thus, the innate microglia greatly enhances the predictive and translational potential of our organoids and allow us to study pathologies involving dysfunctional microglia such as type 2 diabetes (T2D) and Alzheimer disease (AD). It is known that T2D can increase risk of developing AD, but observations from current models (cells, mice) rarely translate through to the clinic. We have generated brain organoids from control donors and donors with AD. Standard Western blotting (SDS-PAGE) analysis of samples collected over 90 days in culture reveals a time-dependent emergence of markers of pathology in the AD organoids, but not in the control organoids. We propose to analyze these same organoids for markers of T2D (e.g., expression and phosphorylation of the Insulin Receptor (IR) and Insulin Receptor Substrate-1 (IRS-1)). This will allow us to determine whether markers of the two diseases align and, if so, whether markers of the one disease precede those of the other. If time permits, we will compare the expression patterns of markers for these two pathologies in a mouse model of AD.