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Abstract Details

Computational modeling of tau pathology spread reveals genetic correlates of regional vulnerability and the impact of a LRRK2 mutation
Aging, Dementia, Cognitive, and Behavioral Neurology
P9 - Poster Session 9 (5:30 PM-6:30 PM)
As neurodegenerative diseases progress, aggregates of misfolded proteins and neuroimaging evidence of atrophy become widespread throughout the brain. Recent findings in a mouse model of Parkinson’s disease suggest that both neuroanatomical connections and regional vulnerability are major contributors to progression. We hypothesized that progression of tau pathology in Alzheimer’s disease (AD) and other tauopathies also occurs via a combination of spread and regional vulnerability.
To assess the contribution of neuroanatomical connectivity, spatial proximity, and regional gene expression to the spread of tau pathology in non-transgenic mice and mice with a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation.
We injected the hippocampi of non-transgenic and LRRK2 G2019S mice with AD tau. Pathology was quantified at 1, 3, 6, and 9 months later across 134 brain regions. We optimized network diffusion models to predict spatial patterns of pathology over time using anatomical connectomes obtained through viral tract tracing. We compared the cross-validated model performance between different model architectures. We defined regional vulnerability as the residual pathology after accounting for predictions from our connectome-based spreading model.
The best performing model consisted of primary retrograde spread and a minor contribution of anterograde spread. Regional vulnerability was spatially correlated with 20 candidate genes after adjustment for multiple comparisons. Our model performed equally well in mice harboring a mutation in LRRK2, yet these mice exhibited an increased preference for retrograde spread and decreased preference for anterograde spread.
Our findings suggest that misfolded tau spreads predominantly in the retrograde direction with a minor contribution of anterograde spread. Retrograde spread is enhanced in mice with a LRRK2 mutation. This study provides a framework for understanding neuropathological progression in tauopathies, and identifies possible molecular targets for therapeutics aimed at altering the spread and accumulation of tau pathology.
Eli Cornblath, MD, PhD (Hospital University of Pennsylvania)
Mr. Cornblath has nothing to disclose.
Howard Liu Li Mr. Li has nothing to disclose.
Lakshmi Changolkar, Other Mrs. Changolkar has received personal compensation for serving as an employee of Univ of Pennsylvania.
Bin Zhang, MD,PhD (University of Pennsylvania) Dr. Zhang has received personal compensation for serving as an employee of University of Pennsylvania.
Hannah Jean Brown, Other Ms. Brown has nothing to disclose.
Ronald James Gathagan, II Mr. Gathagan has nothing to disclose.
Modupe Folaranmi Olufemi Ms. Olufemi has nothing to disclose.
John Q. Trojanowski, MD,PhD (University of PA School of Med) Dr. Trojanowski has nothing to disclose.
Danielle Smith Bassett, PhD (University of Pennsylvania) Prof. Bassett has nothing to disclose.
Virginia Lee, PhD (University of Pennsylvania) Virginia Lee, PhD has nothing to disclose.
Michael Henderson, PhD (Van Andel Institute) The institution of Dr. Henderson has received research support from National Institutes of Health. The institution of Dr. Henderson has received research support from Michael J. Fox Foundation.