Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• The rTg4510 mouse line exhibits a tauopathy-like phenotype attributed to high forebrain expression of mutant human tau (tau P301L).
• Temporal control of transgene expression is a feature of this model.

Purpose of the Study:

• To investigate the sole contribution of mutant human tau overexpression to tauopathy-like phenotypes.
• To identify other genetic factors influencing tauopathy in the rTg4510 mouse line.

Main Methods:

• Comparison of tau P301L overexpression levels and phenotypes between rTg4510 mice and a novel mouse line with targeted transgene insertion.
• Analysis of transgene insertion sites, copy numbers, and associated genomic deletions in rTg4510 mice.

Main Results:

• A novel mouse line with higher tau P301L overexpression than rTg4510 showed delayed atrophy and distinct behavioral profiles.
• The tauopathy phenotype in rTg4510 mice is linked to a large deletion in Fgf14 and a separate deletion disrupting five genes, in addition to transgene overexpression.
• The number of tau transgene copies and the specific insertion locus are critical factors.

Conclusions:

• Mutant human tau overexpression alone is insufficient to fully explain the rTg4510 tauopathy phenotype.
• The genetic background, including large genomic deletions and transgene insertion site, significantly modulates tauopathy development.
• Future studies using rTg4510 must consider these confounding genetic factors for accurate interpretation.