Abstract Details

Title Computational modeling of tau pathology spread reveals genetic correlates of regional vulnerability and the impact of a LRRK2 mutation

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P9 - Poster Session 9 (5:30 PM-6:30 PM)

Poster/Presentation
Number 3-005

Objective 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.

Background 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.

Design/Methods 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.

Results 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.

Conclusions 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.

Authors/Disclosures
Eli Cornblath, MD, PhD (Hospital University of Pennsylvania) PRESENTER	Mr. Cornblath has nothing to disclose.
	No disclosure on file
	No disclosure on file
Bin Zhang (University of Pennsylvania)	No disclosure on file
	No disclosure on file
Ronald J. Gathagan II	Mr. Gathagan has nothing to disclose.
	No disclosure on file
John Q. Trojanowski, MD, PhD (University of PA School of Med)	Dr. Trojanowski has nothing to disclose.
	No disclosure on file
Virginia Lee, PhD (University of Pennsylvania)	Virginia Lee, PhD has nothing to disclose.
	No disclosure on file

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