Unlocking Tau’s Secrets: Human Brain Cells in the Mouse Brain

This project aims to explore the molecular pathways influencing the spread of tau using an innovative human-mouse chimera model that develops tau accumulation.

Dr. Qu has pioneered modeling tau buildup in human neurons using different types of neural cells from stem cells derived from skin biopsy. This study proposes transplanting both human neurons and microglia—the brain’s immune cells—into mouse brains to generate a groundbreaking chimera human-mouse model that develops tau accumulation. Using this model, the study will also examine how human specific molecular pathways affect the disease’s progression. This research could lead to breakthroughs in understanding and treating Alzheimer’s and other tau-related diseases.

This research introduces a groundbreaking Tau-inclusion chimera model that integrates human microglia and neural cells, engineered to express 4R-Tau, offering a more comprehensive representation of tauopathies like Alzheimer’s disease. Advanced techniques like whole-mount staining and single-nucleus RNA sequencing are employed to unravel Tau aggregation and propagation mechanisms. The study also explores the roles of Tau aggregation modifiers like VPS29 and the UFMylation pathway, potentially leading to novel understandings and therapeutic strategies for tauopathies.

This study creates a novel model that reflects the complex cellular interactions observed in Alzheimer’s affected brains, incorporating human microglia, astrocytes, and neurons in Tau propagation. This model offers insights into the molecular mechanisms of diseases and can be applied to drug discovery efforts. By leveraging this novel platform, the study delves into genetic factors influencing Tau aggregation, such as the retromer complex and the UFMylation pathway. These findings may lead to new understandings and therapeutic strategies for tauopathies.