Modification: MAPT: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Mixed background (BALB/c x C57B1/B6 x B6D2F1)
Availability: Mice are no longer available, but frozen ES cells are available through Lars Nilsson or Astrid Gumucio
Tau protein exists in several isoforms, which are differentially expressed according to species, stage of development, and tissue type. Isoforms are often categorized by whether they have four microtubule-binding domains (4R tau) or three microtubule-binding domains (3R tau). 4R tau is made from transcripts that include exon 10, whereas 3R tau excludes exon 10. In the adult human brain, there is a balanced splicing that results in approximately 1:1 expression of 3R and 4R tau. In the mouse brain only 3R tau is present at birth, switching exclusively to 4R tau in adulthood.
These mice provide a system in which to study the functional significance of 4R tau isoforms. Homozygous exon 10 knockouts (E10-/-) lack 4R tau altogether. Heterozygotes (E10+/-) show a humanized expression pattern of tau isoforms with both 3R tau and 4R tau. At one day of age, only 3R tau was detected, but by postnatal day nine equal amounts of 3R and 4R tau were present in the brain. All three major isoforms of 3R tau were present by western blot and the anatomic expression pattern of 3R tau was the same as that of endogenous 4R tau in adult mice (Gumucio et al., 2013).
Homozygous knockouts (E10-/-) showed deficits in Rotarod performance at 13 to 17 months of age compared with E10+/- mice and E10+/+. Their grip strength was also weaker compared with E10+/- mice, but not E10+/+ mice. Homozygous knockout mice were less active at nine to 10 months of age than heterozygous counterparts. Behavioral tests showed no apparent deficits in spatial learning or memory in E10-/- compared with E10+/- mice. Likewise, anxiety behaviors were comparable between genotypes.
At 12 months of age, there were no overt differences in brain structure or gross morphology between the genotypes. Likewise, astrocyte numbers were comparable as assessed by GFAP. There was no evidence of tau aggregation in the brains of E10+/- or E10-/- mice at 12 months of age.
Last Updated: 15 Apr 2016
- Gumucio A, Lannfelt L, Nilsson LN. Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging. BMC Neurosci. 2013 Nov 22;14:148. PubMed.
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