Mouse models of Alzheimer's disease for preclinical research

Most mouse models for preclinical research into Alzheimer's disease (AD) rely on the overexpression paradigm, in which familial AD (FAD)-related genes linked to amyloid precursor protein (APP) and presenilin-1 (PSEN1) are overexpressed. Such mice have been used for over two decades as the first-generation transgenic lines for AD, with animals exhibiting AD pathologies along with additional phenotypes, leading to the serious artifacts. To overcome the intrinsic drawbacks of the overexpression paradigm, we previously developed second-generation mouse models that incorporate humanized amyloid β (Aβ) sequences and several FAD-related mutations on the mouse endogenous App gene. Such models show AD pathologies in an age-dependent manner. In addition, our group recently generated additional lines of mice harboring multiple mutations without gene overexpression; these third-generation models exhibit an accelerated AD pathology compared to earlier generations. In this review, we describe the development and future prospects of AD mouse models in terms of their scientific properties and therapeutic perspectives in the context of the preclinical study of AD.