Transgenic mouse models have also been troubled by the difficulty of producing the full spectrum of AD pathologies, including neuronal loss. For example, neither PDAPP nor Tg2576 mice, despite having extensive amyloid deposition, exhibit neuronal loss.53,54 APP23 mice show only modest losses of cornu ammonis 1 pyramidal cells (about 15%),55 losses that are far less than those observed in AD. More substantial neuronal loss has been reported in mice expressing multiple PS1 and APP mutations.56–58 For example, mice harboring 2 APP and 1 PS1 FAD mutation show a 35% loss of hippocampal neurons.57 In another study, 2 APP mutations (APP-Swedish/APP-London) expressed from transgenes were crossed onto a mouse line that had 2 presenilin FAD mutations (M233T/L235P) knocked into the mouse PS1 gene. Besides amyloid pathology, extensive neuronal loss (>50%) occurred in the hippocampus.56 Finally, 3 APP and 2 PS1 FAD mutations recently were combined to create a 5X FAD mutant mouse, and grossly apparent neuronal loss was observed.58 Thus, neuronal loss can be induced in the mouse but only, it would seem, by the combination of multiple mutations that individually are sufficient to cause disease in humans.
