Develop a human-mouse chimeric brain model for studying tau pathology in human neuron in vivo

Project Summary/Abstract Alzheimer’s disease (AD) is the most common cause of dementia, affecting 6.7 million Americans aged 65 and older. Tau pathology, characterized by the abnormal aggregation of tau protein, is a prominent pathological hallmark of AD that shows the strongest correlation with cognitive decline compared to other AD pathological

hallmarks. However, current tau models have limitations in replicating tau pathology observed in AD brains, and most therapies targeting tau developed in animal models have failed in clinical trials, largely due to species differences. This underscores the urgent need to develop translational human cell-centric tau models capable of

addressing the critical gap in understanding the mechanisms underlying tau pathology, particularly its spatiotemporal formation and spread, and its relationship with cognitive decline in AD. The long-term goal is to create tau models in human neurons in vivo to investigate mechanisms of tau pathology and develop therapeutic

interventions for tau pathology in AD and other tauopathies. In a recent study, we successfully generated a unique human-mouse chimeric brain model that enables the maturation, aging, and survival of human neurons for over 18 months. Furthermore, human neurons are widely distributed and functionally integrated into the host

brain. Based on these results and the seeding activity of pathological tau, which can induce normal tau misfolding and form tau pathology, we hypothesize that injecting pathological tau protein isolated from AD postmortem brain tissues into chimeric mouse brains will result in tau pathology in human neurons in vivo. The objective of

this project is to develop a human-mouse chimera tau seeding model that recapitulates human tau pathology in human neurons in vivo without introducing MAPT mutations, and that can be used to investigate the spatiotemporal formation and spread of tau pathology in human neurons and monitor associated cognitive

dysfunction. Additionally, we aim to elucidate transcriptomic signatures of human neurons during tau pathology progression to gain deeper mechanistic insights. Furthermore, we will compare tau pathological endpoints between human and mouse neurons within the same brain environment using the chimera model. We propose

the following aims. Aim 1: To characterize a human-mouse chimera tau seeding model in terms of species- specific spatiotemporal patterns of tau pathology and associated cognitive dysfunction. Aim2: To determine disrupted cellular pathways and identify species-specific transcriptomic perturbations associated with tau

pathology progression in human neurons using the chimeras. The successful completion of this project will advance our understanding of tau pathology and lead to a novel human-mouse chimeric brain model for studying tau pathology in human neurons in vivo. This innovative model will be a valuable pre-clinical tool for

understanding human tau pathology and testing interventions targeting tau pathology in AD and other tauopathies.