Single App knock-in mouse models of Alzheimer's disease

Abstract

Experimental studies of Alzheimer's disease have largely depended on transgenic mice overexpressing amyloid precursor protein (APP). These mice, however, suffer from artificial phenotypes because, in addition to amyloid β peptide (Aβ), they overproduce other APP fragments. We generated knock-in mice that harbor Swedish and Beyreuther/Iberian mutations with and without the Arctic mutation in the APP gene. The mice showed typical Aβ pathology, neuroinflammation and memory impairment in an age-dependent manner.

APP mouse models for Alzheimer's disease preclinical studies

“…Due to the increase in CTF‐β and concomitant decrease of CTF‐α in the App knock‐in mice, the total amount of CTF in App knock‐in mice remains the same as in wild‐type mice. To examine the effect of increased CTF‐β and s APP β in this case, App NL mice were generated that carried only the Swedish mutation and we confirmed that this amount of CTF‐β and s APP β exert no effects on the pathology or cognitive function of the mice (Saito et al , 2014; Masuda et al , 2016). The high levels of Aβ 42 in App NL‐F mice led to pathological Aβ deposition in the cerebral cortex and hippocampus, which was accompanied by enhanced neuroinflammation, that is, infiltration of astrocytes and microglia that surround plaques from 6 months of age.…”

“…Crossbreeding with other mutant mice can generate additional artificial phenotype(s) (Higuchi et al , 2012; Saito et al , 2014). Refer to section “Limitations of first‐generation mouse models” for details.…”

“…The exception was that App knock‐in mice produced more CTF‐β and thus s APP β compared with wild‐type mice because of the Swedish mutation (Saito et al , 2014). Due to the increase in CTF‐β and concomitant decrease of CTF‐α in the App knock‐in mice, the total amount of CTF in App knock‐in mice remains the same as in wild‐type mice.…”

“…There is no evidence for an interaction between the Swedish mutation and Beyreuther/Iberian mutations, but the Arctic mutation increases CTFs (CTF‐β + CTF‐α) by 50% by unknown mechanisms (T Saito & TC Saido, unpublished; Cheng et al , 2004) and results in an unnatural Aβ conformation. It is important to perform delipidation pretreatment for the analysis of CTFs (Sato et al , 2003; Saito et al , 2014). …”

“…For example, KPI domain‐containing APP variants are not expressed in mouse brain unlike in human brain (Saito et al , 2014). Therefore, App knock‐in mice may not be suitable for addressing the properties of KPI domain‐containing APP variants in endothelial cells, since these variants are expressed mostly in endothelial cells (Kitazume et al , 2010).…”