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
Affiliations
Lindsay A. Welikovitch
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
Simon Dujardin
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
Amy R. Dunn
The Jackson Laboratory, Bar Harbor, ME 04609, USA
Analiese R. Fernandes
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Anita Khasnavis
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Lori B. Chibnik
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Catherine C. Kaczorowski
The Jackson Laboratory, Bar Harbor, ME 04609, USA; Corresponding author
Bradley T. Hyman
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: 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.
