Transgenic mice have been used to study many aspects of AD pathophysiology. Two recent examples of their usefulness are studies designed to test differences in the in vivo effects of Aβ40 and Aβ42. In vitro, Aβ42 is more amyloidogenic than Aβ40.67 However, Aβ40 is found in plaque amyloid and is especially common in vascular amyloid.68 In vitro studies have suggested, however, that Aβ42 deposition is necessary in order to seed Aβ40-containing deposits.69 To test the relative plaque-forming propensity in vivo, transgenic mice were generated that selectively express either Aβ40 or Aβ42.70 These mice were created by the fusion of Aβ40 and Aβ42 coding sequences to the C-terminus of the BRI protein associated with familial British dementia. BRI is a transmembrane protein that undergoes constitutive cleavage near its C-terminus that releases a soluble 23–amino acid peptide. Aβ40 or Aβ42 selective expression systems were created by the replacement of the 23–amino acid BRI peptide region with human Aβ40 or Aβ42 sequences. Thus, in the fusion construct, cleavage, rather than releasing the native BRI peptide, releases either human Aβ40 or Aβ42. Although highly
