TAPP and 3xTg-AD thus exhibit a broader spectrum of AD pathologies. The question, however, again arises: are these models of AD? They do exhibit the much sought after plaques with a tangle pathology. However, they represent a composite of 2 distinct diseases that do not naturally occur together. Plaque development is almost certainly driven by the APP and PS1 FAD mutations, whereas the tangle-like pathology is driven by the tau mutations. Indeed, in 3xTg-AD mice, the pathologies arise in spatially distinct patterns, with Aβ deposition starting in the neocortex and appearing later in the hippocampus, whereas tau pathology progresses in the opposite direction, beginning in the hippocampus and appearing later in the neocortex.63 It does, however, appear that the mutations interact because in TAPP mice, NFTs are found in regions that rarely or never exhibit NFTs in singly transgenic JPNL3 animals. In addition, intracerebral injections of anti-Aβ antibodies into the hippocampus of 3xTg-AD mice not only reduced Aβ accumulation but also resulted in clearance of early-stage tau pathology, although later-stage lesions were resistant.65 These studies thus show that modulating Aβ
