Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains

Lindsay A Welikovitch; Simon Dujardin; Amy R Dunn; Analiese R Fernandes; Anita Khasnavis; Lori B Chibnik; Catherine C Kaczorowski; Bradley T Hyman

doi:10.1016/j.isci.2023.105983

Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains

iScience. 2023 Jan 14;26(2):105983. doi: 10.1016/j.isci.2023.105983. eCollection 2023 Feb 17.

Authors

Lindsay A Welikovitch^{1

2}, Simon Dujardin^{1

2}, Amy R Dunn³, Analiese R Fernandes¹, Anita Khasnavis¹, Lori B Chibnik⁴, Catherine C Kaczorowski³, Bradley T Hyman^{1

2}

Affiliations

¹ Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
² Harvard Medical School, Boston, MA 02115, USA.
³ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Abstract

The speed and scope of cognitive deterioration in Alzheimer's disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline.

Keywords: Cellular neuroscience; Molecular neuroscience; Neurogenetics.

Abstract

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