Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ∼60-70% of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing β-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5% of patients with Alzheimer disease have familial Alzheimer disease—that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble β-amyloid oligomers in disease pathogenesis, as well as of the relationship between β-amyloid and Tau pathologies.