Lewis et al.62 first crossed a transgenic line known as JPNL3, which expresses the P301L mutation associated with FTDP-17, with Tg2576 mice. Singly transgenic JPNL3 mice were known to develop NFT-like lesions, and bigenic mice [tau amyloid precursor protein (TAPP) mice] exhibited NFTs and amyloid plaques. More recently, Oddo et al.63 generated a triply transgenic model (3xTg-AD) by coinjecting 2 transgenes containing APP-Swedish and P301L FTDP-17 mutations into fertilized eggs harvested from PS1M146V knock-in mice. The resulting transgenic lines thus expressed mutations in APP and tau from exogenous transgenes combined with a PS1 FAD mutation from the endogenous mouse gene. With aging, these mice had increased Aβ40 and Aβ42 levels. Intraneuronal Aβ accumulated, and the mice exhibited amyloid plaques and NFT-like lesions that immunostained with antibodies recognizing conformationally altered tau epitopes. Amyloid plaques were apparent by 6 months of age and preceded tau pathology, which was not evident until about 1 year of age. Functionally, 3xTg-AD mice developed age-dependent synaptic dysfunction, including altered long-term potentiation and deficits in spatial memory.63,64
