Introducing Human APOE into Aβ Transgenic Mouse Models

Apolipoprotein E (apoE) and apoE/amyloid- β (A β ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE −/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for A β -independent apoE effects on neurodegeneration. To determine the effects of apoE on A β -induced neuropathology, apoE −/− mice were crossed with A β -Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE −/− /A β -Tg mice further delayed plaque deposition, which eventually developed in apoE4/A β -Tg mice prior to apoE3/A β -Tg. One approach to address h APOE -induced temporal delay in A β pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with A β -Tg mice that have rapid-onset A β pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/A β -Tg mice. Thus, tractable models for human-apoE/A β -Tg mice continue to evolve.