Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque–bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque–associated tau pathogenesis.
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We thank S. Kim, B. Zoll, H. Brown, F. Bassil, J. Robinson, T. Schuck and M. Byrne for technical assistance. We thank W. O'Brien and the Penn Neurobehavioral Testing Core for help with behavior tests, S. Xie for help with statistical analyses and E. Lee for helpful comments. We thank N. Kanaan (Michigan State University) for providing TOC1 antibody, which was generated and initially provided by L. Binder (deceased), P. Davies (Hofstra Northwell School of Medicine) for contributing PHF1, MC1 and TG3 antibodies, and M. Goedert (University of Cambridge) for contributing pS422 antibody. T. Saido (RIKEN Brain Science Institute) is thanked for providing APP-KI mice. This work was funded by National Institute on Aging (NIA) AG10124 (J.Q.T.), AG17586 (V.M.-Y.L.), AG017628 (T.A.), CurePSP (J.Q.T.) and the Woods Foundation (V.M.-Y.L.).
The authors declare no competing financial interests.
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He, Z., Guo, J., McBride, J. et al. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24, 29–38 (2018). https://doi.org/10.1038/nm.4443
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