Mutations: APP KM670/671NL, APP I716F (Iberian), APP E693G (Arctic)
Modification: APP: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: Apptm3.1Tcs/Apptm3.1Tcs
Genetic Background: C57BL/6
Availability: Available through Takaomi Saido
Untangling the effects of elevated Aβ from those due to APP overexpression is a common challenge when interpreting the phenotypes of APP transgenic mice. The APPNL-G-F model avoids potential artifacts introduced by APP overexpression by using a knock-in approach to express APP at wild-type levels and with appropriate cell-type and temporal specificity. APP is not overexpressed, but levels of pathogenic Aβ are elevated due to the combined effects of three mutations associated with familial Alzheimer's disease. Specifically, the APP construct, which contains a humanized Aβ region, includes the Swedish “NL”, the Iberian “F”, and the Arctic “G” mutations. These mutations promote Aβ toxicity by increasing total Aβ production (Swedish mutation), increasing the Aβ42/Aβ40 ratio (Iberian mutation), and promoting Aβ aggregation through facilitating oligomerization and reducing proteolytic degradation (Arctic mutation).
Like the related APPNL-F mice, which express the Swedish and Iberian mutations, APPNL-G-F mice accumulate Aβ and recapitulate several AD-associated pathologies, including amyloid plaques, synaptic loss, and microgliosis and astrocytosis, especially in the vicinity of plaques. The presence of the Arctic mutation accelerates the pathology relative to APPNL-F mice, and leads to particularly severe phenotypes. Aβ deposition is observed starting at two months and is nearly saturated by seven months. In contrast to APPNL-F mice, the APPNL-G-F mice develop subcortical amyloidosis in addition to cortical amyloidosis, consistent with the neuropathology observed in patients with the Arctic mutation. Neurofibrillary tangles and neurodegeneration are not detected (Saito et al., 2014), although phosphorylated tau is elevated in dystrophic neurites around plaques (personal communication, Takaomi Saido).
The mice also display age-associated cognitive impairment, specifically memory impairment as measured by the Y maze starting at six months. The cognitive impairment in APPNL-G-F mice is more severe than the impairment in APPNL-F mice, occurring about three times faster.
Available to nonprofit organizations with MTA and for-profit organizations with license. Contact Takaomi Saido.
APPNL (Swedish mutation only)
APPNL-F (Swedish and Iberian mutations)
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
- Changes in LTP/LTD
Aggressive amyloidosis; plaques develop in homozygous mice starting at 2 months with near saturation by 7 months. Aβ deposition at 4 months in heterozygous mice. Cortical and subcortical amyloidosis present.
Absent; although phosphorylated tau is elevated in dystrophic neurites around plaques.
Microglia and activated astrocytes accumulate with age starting around 2 months, especially around plaques in a manner concurrent with plaque formation.
Reduction of synaptophysin and PSD95 immunoreactivities associated with Aβ plaques in both cortical and hippocampal areas.
Changes in LTP/LTD
Memory impairment in homozygous mice by 6 months of age as measured by the Y maze.
- Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.