Developing a better mouse model of Alzheimer disease with clinically relevant phenotypes in tau pathology

OBJECTIVE Transgenic mouse model has been widely used in pathogenesis study and preclinical drug evaluation in Alzheimer disease(AD).However,key differences are found between current animal models and clinical AD patients regarding phenotypes.Lack of complete models that recapitulate broad spectrum of human AD neuropathology restricts efficacy of research projects and leads to frequent failure in AD drug development at clinical trial stages.This study aims to develop better mouse models of AD through modifying key phenotype insufficiency.METHODS By crossing different single and double transgenic mice with different mutations of APP/PS1 or tau and under prion,Thy1 or PDGF-β promoter,as well as selected knockout mice,I produced a dozen of bigenic models for neuropathology screening.Further neurochemical,behavioral and pharmacological validations were conducted in the optimized mouse model.RESULTS Neuropathology phenotyping found remarkable differences in tau pathology and neurodegeneration among individual APP/PS1/tau transgenic models.I had identified a triple mouse model named FADT that showed(1) huge mature tau pathology in hippocampus and cortex;(2) abundant tau truncation,as seen in human AD brain;(3)progressive neurodegeneration;(4)selective brain atrophy in hippocampus and entorhinal cortex;(5) reproducible and late onset spatial memory defects,etc.Importantly,remarkable tau pathology in this FADT model is mainly driven by beta-amyloid pathology,which differs from high expression of tau in rTg4510 model.CONCLUSION I had developed a new triple transgenic mouse model that recapitulates broad spectrum of human AD neuropathology features.This study will not only establish a solid model basis for AD pathophysiology investigation and drug development,but also reveal important clues on the interaction of beta-amyloid and tau pathologies in the brain.