ABSTRACT

Several transgenic models have been generated that recapitulate key elements of AD neuropathology, but to date, no model fully mimics the complete neuropathological spectrum.12 Although a single missense mutation in either the APP, PS1, or PS2 gene is sufficient to induce an aggressive form of AD in humans, this has not been the case following the introduction of these mutant alleles into genetically modified mice. Likewise, Down’s syndrome patients, who harbor an increased concentration of the APP gene, almost invariably develop the complete gamut of AD neuropathology by their fifth decade.13,14

Whereas mutant APP overexpression in transgenic mice allows for the successful modeling of amyloid deposition, surprisingly, the introduction of missense mutations in the APP, PS1, or PS2 genes (or their increased expression) has generally proved insufficient for inducing the complete spectrum of AD neuropathology in genetically altered mice – most notably characterized by the paucity of neurofibrillary pathology. Consequently, the development of both plaques and tangles has

required aggressive biotechnological approaches, such as the development of genetically modified mice harboring multiple transgenes.