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

Award Number: R21NS140907
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $157,000 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/28/2025	NON-COMPETING CONTINUATION	$157,000
														Subtotal = $157,000

Issue Date FY: 2024 ( Subtotal = $274,750 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2024	NEW	$274,750
														Subtotal = $274,750

Grand Total All Awards = $431,750

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

Award Number: R21NS140907

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/17/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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