Recent Advances in the Modeling of Alzheimer’s Disease

• Published in: Frontiers in Neuroscience
• Main Authors: Sasaguri, Hiroki, Hashimoto, Shoko, Watamura, Naoto, Sato, Kaori, Takamura, Risa, Nagata, Kenichi, Tsubuki, Satoshi, Ohshima, Toshio, Yoshiki, Atsushi, Sato, Kenya, Kumita, Wakako, Sasaki, Erika, Kitazume, Shinobu, Nilsson, Per, Winblad, Bengt, Saito, Takashi, Iwata, Nobuhisa, Saido, Takaomi C.
• Format: Text
• Language: English
• Published: Frontiers Media S.A. 2022
• Subjects: Neuroscience; Arctic
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009508/; https://doi.org/10.3389/fnins.2022.807473

Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP/presenilin 1 (PS1) cDNA is overexpressed (1st generation models). Although many of these models successfully recapitulate major pathological hallmarks of the disease such as amyloid β peptide (Aβ) deposition and neuroinflammation, they have suffered from artificial phenotypes in the form of overproduced or mislocalized APP/PS1 and their functional fragments, as well as calpastatin deficiency-induced early lethality, calpain activation, neuronal cell death without tau pathology, endoplasmic reticulum stresses, and inflammasome involvement. Such artifacts bring two important uncertainties into play, these being (1) why the artifacts arise, and (2) how they affect the interpretation of experimental results. In addition, destruction of endogenous gene loci in some Tg lines by transgenes has been reported. To overcome these concerns, single App knock-in mouse models harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (App(NL–G–F) and App(NL–F) mice) were developed (2nd generation models). While these models are interesting given that they exhibit Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner, the model with the Artic mutation, which exhibits an extensive pathology as early as 6 months of age, is not suitable for investigating Aβ metabolism and clearance because the Aβ in this model is resistant to proteolytic degradation and is therefore prone to aggregation. Moreover, it cannot be used for preclinical immunotherapy studies owing to the discrete affinity it shows for anti-Aβ antibodies. The weakness of the latter model (without the Arctic mutation) is that the pathology may require up to 18 months before it becomes sufficiently apparent for experimental investigation. Nevertheless, this model was successfully applied to modulating Aβ pathology by genome editing, to revealing the ...