Human "Mini-Brains" to Study Alzheimer's and Progressive Supranuclear Palsy

The goal of this project is to understand the similarities and differences in the cellular and neuronal network vulnerability between Alzheimer’s disease and progressive supranuclear palsy.

Aim 1: To compare the propensity for propagation of different tau strains using human cerebral organoids (COs). This helps us understand if pathological tau strains accumulate and propagate in COs and which cell types are responsible for this effect. Aim 2: To determine how and if different pathological tau strains affect the electrophysiological properties in COs. Intracellular calcium activity and spontaneous extracellular field potentials will be measured. Aim 3: To compare the transcriptomic profile of human COs before and after the treatment of different tau strains using scRNA-Seq.

The organoid platform of human cerebral organoids for studying the propagation of tau pathology and mechanisms underlying the selective cellular and network vulnerability to tau pathology in AD and PSP is novel and innovative.

The successful completion of this study will establish a human-relevant organoid model to study the cellular and neuronal network vulnerability in AD and PSP. The results will also help understand the molecular mechanisms underlying the cellular and neuronal network vulnerability in these two diseases. In addition, it will provide useful insights for developing new therapeutics of protecting those vulnerable neurons against insults from tau pathology.