Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains. iScience. 2023;26(2):105983
This research is supported by the National Institutes of Health (R01AG057914, R01AG054180, and RF1AG063755 to C.C.K.; 1RF1AG058674-01 to B.T.H.); the BrightFocus Foundation (A2016397S to C.C.K.); the Alzheimer’s Association (ZEN-21-846037 to C.C.K.); and the JCB Foundation. L.A.W. is the recipient of Postdoctoral Fellowships from the Canadian Institutes of Health Research and the Fonds de Recherche du Que ́ bec - Sante ́ .
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.