Genes: App, MAPT
Mutations: APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic)
Modification: App: Knock-In; MAPT: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Available through Takaomi Saido, RIKEN Center for Brain Science.
AppNL-G-F/MAPT double knock-in mice represent a unique model for studying the nexus between human Aβ and human tau. These mice were created by crossing AppNL-G-F mice with MAPT knock-in mice. In the former line, 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. In the MAPT knock-in line, the entire genomic sequence of murine Mapt from exon 1 to exon 14 was replaced with the human MAPT sequence. In AppNL-G-F/MAPT double knock-in mice, the expression of the App and MAPT genes is under the control of natural regulatory elements, mice express normal levels of APP and tau, the presence of the entire genomic sequences permits alternative splicing, and animals lack endogenous mouse tau that could interact with human tau.
Like MAPT knock-ins, AppNL-G-F/MAPT double knock-in mice express both 3R (contains three microtubule-binding domains) and 4R isoforms of human tau, with the level of 4R mRNA approximately 70 percent that of 3R mRNA.
Like both the AppNL-G-F and MAPT knock-in lines, AppNL-G-F/MAPT double knock-in mice lack neurofibrillary tangles and do not exhibit neurodegeneration. While double knock-in mice display amyloid plaques, plaque-associated neuritic dystrophy, neuroinflammation, and memory deficits, these traits are no more pronounced in the double knock-ins than in AppNL-G-F mice. Tau phosphorylation is increased in the AppNL-G-F/MAPT double knock-ins, compared with MAPT knock-ins, but is similar to that of AppNL-G-F mice. Thus, replacing mouse tau with human tau does not appear to exacerbate the pathology seen in AppNL-G-F mice.
AppNL-G-F/MAPT double knock-in mice have been used to study the spread of pathological tau in the brain. Compared with AppNL-G-F mice, double knock-in mice showed accelerated propagation of pathological tau (AT8-immunoreactive) species after AD-derived tau was injected into the mouse brain.
AppNL-G-F. The mouse App sequence was modified to contain a humanized Aβ region and three pathogenic mutations (Swedish, Iberian, and Arctic).
MAPT knock-in. 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).
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
- Synaptic Loss
- Changes in LTP/LTD
Plaques observed at 2 months.
No neurofibrillary tangles observed up to 24 months of age.
No neurodegeneration observed up to 24 months of age.
Astrogliosis and microgliosis observed by 4 months.
Changes in LTP/LTD
Deficits in the Y-maze test of working memory at 12 months of age.
Last Updated: 13 Aug 2019