Modeling a TREM2 Alzheimer’s risk variant in brain organoids and microglia
Alzheimer’s disease is the leading cause of dementia in older adults, affecting nearly 7 million patients in the US and millions more worldwide. Recent research indicates that microglia, a type of macrophage involved in the brain’s inflammatory response, play a significant role in Alzheimer’s progression. In later stages of the disease, activated microglia can become pro-inflammatory and begin contributing to chronic inflammation in the brain. In this study, brain organoids and microglia containing an Alzheimer’s associated TREM2 mutation, which negatively affects microglia, were cultured together to observe the transition of microglia from a homeostatic state to a pro-inflammatory state. Brain organoids were successfully cultured for 173 days and co-cultured with microglia for 10 days. Immunofluorescence imaging of the co-culture, compared to a wild type (WT) control, revealed that microglia had incorporated throughout the organoids, with phosphorylated-Tau present in both WT and TREM2 co-cultures. However, pTau was detected inside microglia only in the WT organoids. Single-cell RNA sequencing, bulk RNA sequencing and protein analysis are currently in progress to observe differences in transcriptome and protein expression at different time points for both the TREM2 and WT cultures. This organoid-microglia model may provide more insights into Alzheimer’s progression, leading to the development of better treatments and therapies in the future.
