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.
