Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) and hyperphosphorylated tau protein. To develop preventive, diagnostic, and therapeutic strategies for AD, it is essential to establish animal models that recapitulate the pathophysiological process of AD. In this review, we will summarize the advantages and limitations of various mouse models of AD, including transgenic, knock-in, and injection models based on Aβ and tau. We will also discuss other mouse models based on neuroinflammation because recent genetic studies have suggested that microglia are crucial in the pathogenesis of AD. Although each mouse model has its advantages and disadvantages, further research on AD pathobiology will lead to the establishment of more accurate mouse models, and accelerate the development of innovative therapeutics.

Amyloid-β (Aβ) deposition in the brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD). We have previously identified amyloid precursor protein (APP)669-711 (a.k.a. Aβ(-3)-40) in human plasma using immunoprecipitation combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (IP-MALDI-MS). Furthermore, we found that the level of a composite biomarker, i.e., a combination of APP669-711/Aβ1-42 ratio and Aβ1-40/Aβ1-42 ratio in human plasma, correlates with the amyloid PET status of AD patients. However, the production mechanism of APP669-711 has remained unclear. Using in vitro and in vivo assays, we identified A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) as a responsible enzyme for APP669-711 production. ADAMTS4 cleaves APP directly to generate the C-terminal stub c102, which is subsequently proteolyzed by γ-secretase to release APP669-711. Genetic knockout of ADAMTS4 reduced the production of endogenous APP669-711 by 30% to 40% in cultured cells as well as mouse plasma, irrespectively of Aβ levels. Finally, we found that the endogenous murine APP669-711/Aβ1-42 ratio was increased in aged AD model mice, which shows Aβ deposition as observed in human patients. These data suggest that ADAMTS4 is involved in the production of APP669-711, and a plasma biomarker determined by IP-MALDI-MS can be used to estimate the level of Aβ deposition in the brain of mouse models.