Chapter 3 - Current mouse models of Alzheimer’s disease for investigating therapeutic agents

Alzheimer’s disease (AD) is the most common neurodegenerative disease with more than 50 million patients worldwide. The pathophysiology of the disease is complicated involving cholinergic neurodegeneration and neuronal loss, neuroinflammation and oxidative stress as well as two hallmarks, namely amyloid beta (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles (NFTs). There is an unmet medical need in AD calling for the development of new therapeutic interventions, which requires relevant disease animal models to evaluate new chemical entities in preclinical research. Based on current understanding of the disease, a number of commonly used mouse models of AD have been established, which will be introduced in this chapter. These models can be loosely classified into two categories. One is transgenic models carrying mutations of key pathogenic proteins, and the other one is non-genetic models in which the pathological states were chronically or acutely induced by chemicals. Particular attention is focused on the generation method, main pathological features, and applications of these models in the assessment of therapeutic agents. It is noted that none of these models were able to completely reproduce all the clinical symptoms of the disease, which may, in turn, contribute to the high failure rate of the therapeutic agents in later clinical evaluations. Finally, the shortcomings of current mouse models are discussed. Some selection principles are suggested to avoid subjective factors in animal experiments with the hope to improve the translational predictability.