TY - JOUR T1 - Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation JF - bioRxiv DO - 10.1101/2020.10.13.337857 SP - 2020.10.13.337857 AU - Michael X. Henderson AU - Eli J. Cornblath AU - Howard L. Li AU - Lakshmi Changolkar AU - Bin Zhang AU - Hannah J. Brown AU - Ronald J. Gathagan AU - Modupe F. Olufemi AU - Danielle S. Bassett AU - John Q. Trojanowski AU - Virginia M.Y. Lee Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/14/2020.10.13.337857.abstract N2 - Tau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.Competing Interest StatementThe authors have declared no competing interest. ER -