Modification: MAPT: Knock-In
Disease Relevance: Alzheimer's Disease, Other Tauopathy
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Available through Takaomi Saido, RIKEN Center for Brain Science.
It has been suggested that differences in mouse and human tau may partially underlie the difficulty in modeling Alzheimer’s disease in mice (see Alzforum webinar). In this knock-in model, the entire genomic sequence of murine Mapt from exon 1 to exon 14 was replaced with the human MAPT sequence. These mice express all of the six possible MAPT transcripts, and lack mouse tau that could potentially interact with human tau. Because the expression of the transgene is under the control of Mapt’s natural regulatory elements, tau is expected to be expressed at physiological levels with normal cellular and temporal specificity.
Alternative splicing results in six tau isoforms, which are classified according to whether they contain three (3R) or four (4R) microtubule-binding domains. While all six isoforms are found in the adult human brain, adult mice normally express only 4R isoforms. Like humans, adult MAPT knock-in mice express all six tau isoforms, with the level of 4R mRNA approximately 70 percent that of 3R mRNA.
Tau protein shows normal localization to axons in MAPT knock-in mice.
There is no evidence of increased neuroinflammation, neuronal death, or brain atrophy in MAPT knock-in mice, compared with wild-type mice, at least up to two years of age. Levels of Aβ40 and Aβ42 are also similar in MAPT knock-in mice and wild-type animals. Male MAPT knock-in and wild-type mice do not differ in performance in the Y-maze test of working memory, when tested at one year of age (data from females are not yet available).
These mice have been used to study the spread of pathological tau in the brain. Compared with wild-type mice, MAPT knock-in mice showed accelerated propagation of pathological tau (AT8-immunoreactive) species after AD-derived tau was injected into the mouse brain.
Homologous recombination was used to replace the entire genomic sequence of murine Mapt (from exon 1 to exon 14) with the human MAPT gene from the ATG codon of exon 1 to the 3'-untranslated region (H2 haplotype; NCBI Reference Sequence: NG_007398).
AppNL-G-F/MAPT double knock-in. To study the interactions between amyloid and tau, MAPT knock-in mice were crossed with AppNL-G-F mice, in which the endogenous mouse App gene was modified to contain a humanized Aβ sequence, as well as the Swedish, Arctic, and Iberian mutations linked to AD. Humanization of the MAPT gene did not exacerbate amyloid pathology, neuroinflammation, or neuronal cell death in the double knock-ins, compared with AppNL-G-F mice.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Cognitive Impairment
- Synaptic Loss
- Changes in LTP/LTD
No amyloid plaques at 24 months of age.
No neurofibrillary tangles at 24 months of age.
Neurodegeneration not apparent up to 2 years of age.
No astrogliosis or microgliosis observed at 24 months.
Changes in LTP/LTD
At 12 months of age, MAPT knock-in mice perform similarly to wild-type mice in the Y-maze test of working memory (only males tested).
Last Updated: 13 Aug 2019