Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

View ORCID ProfileMichael X. Henderson, Eli J. Cornblath, Howard L. Li, Lakshmi Changolkar, Bin Zhang, Hannah J. Brown, Ronald J. Gathagan, Modupe F. Olufemi, View ORCID ProfileDanielle S. Bassett, John Q. Trojanowski, Virginia M.Y. Lee
doi: https://doi.org/10.1101/2020.10.13.337857
Michael X. Henderson
9Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michael X. Henderson
  • For correspondence: michael.henderson@vai.org
Eli J. Cornblath
2Department of Bioengineering, School of Engineering & Applied Science
4Department of Neuroscience, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Howard L. Li
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lakshmi Changolkar
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bin Zhang
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hannah J. Brown
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ronald J. Gathagan
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Modupe F. Olufemi
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Danielle S. Bassett
2Department of Bioengineering, School of Engineering & Applied Science
3Department of Electrical & Systems Engineering, School of Engineering & Applied Science
5Department of Physics & Astronomy, College of Arts & Sciences
6Department of Psychiatry, Perelman School of Medicine
7Department of Neurology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, 19104 USA
8Santa Fe Institute, Santa Fe, NM 87501 USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Danielle S. Bassett
John Q. Trojanowski
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Virginia M.Y. Lee
1Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 14, 2020.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation
Michael X. Henderson, Eli J. Cornblath, Howard L. Li, Lakshmi Changolkar, Bin Zhang, Hannah J. Brown, Ronald J. Gathagan, Modupe F. Olufemi, Danielle S. Bassett, John Q. Trojanowski, Virginia M.Y. Lee
bioRxiv 2020.10.13.337857; doi: https://doi.org/10.1101/2020.10.13.337857
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation
Michael X. Henderson, Eli J. Cornblath, Howard L. Li, Lakshmi Changolkar, Bin Zhang, Hannah J. Brown, Ronald J. Gathagan, Modupe F. Olufemi, Danielle S. Bassett, John Q. Trojanowski, Virginia M.Y. Lee
bioRxiv 2020.10.13.337857; doi: https://doi.org/10.1101/2020.10.13.337857

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (2414)
  • Biochemistry (4773)
  • Bioengineering (3319)
  • Bioinformatics (14626)
  • Biophysics (6616)
  • Cancer Biology (5156)
  • Cell Biology (7402)
  • Clinical Trials (138)
  • Developmental Biology (4340)
  • Ecology (6858)
  • Epidemiology (2057)
  • Evolutionary Biology (9876)
  • Genetics (7328)
  • Genomics (9496)
  • Immunology (4533)
  • Microbiology (12627)
  • Molecular Biology (4918)
  • Neuroscience (28205)
  • Paleontology (198)
  • Pathology (802)
  • Pharmacology and Toxicology (1380)
  • Physiology (2011)
  • Plant Biology (4473)
  • Scientific Communication and Education (974)
  • Synthetic Biology (1295)
  • Systems Biology (3903)
  • Zoology (722)