In AD, the 39– to 42–amino acid Aβ peptide deposits in senile plaques.7 The Aβ peptide itself is derived from the processing of a larger precursor protein known as the amyloid precursor protein (APP). Many in vitro and in vivo studies have demonstrated that, in particular, the longer Aβ42 species can be neurotoxic. The amyloid cascade hypothesis postulates that shunting of amyloid precursor protein (APP) processing toward Aβ production sets off a chain of pathological events,7 a process that can be modeled in transgenic animals. In addition, although most cases of AD occur sporadically, autosomal dominant forms of the disease exist that mimic the sporadic disease clinically and pathologically. Mutations in 3 genes including APP have been identified as causing familial Alzheimer’s disease (FAD).8 Indeed, the amyloid hypothesis was greatly bolstered by the finding that mutations in APP can cause FAD. These familial cases thus provide a genetic lesion that has been used to advantage in AD modeling in transgenic animals.
