29 Jul 1999

In the August issue of Nature Neuroscience, Bruce Lamb and his associates at Case Western report that they have transferred complete copies of genes for mutant human APP and PS-1 into mice that subsequently produce high levels of Aβ and eventually show widespread fibrillar Aβ deposition. Paralleling their earlier success of using yeast artificial chromosomes to transfer complete human APP genes to mice, the authors inserted single copies of the complete, unrearranged gene for human PS-1, along with segments upstream and downstream of the gene, including the natural transcriptional regulatory elements. Consequently, these mice express the entire spectrum of PS-1 mRNAs and proteins. By contrast, previous, cDNA-based transgenic PS-1 models were created from fragments of the human genes and expressed only single forms of the protein. In this study, the authors show that their hemizygous mutant APP mice develop Aβ deposits, and that homozygotes and APP/PS-1 crosses develope Aβ deposits as early as seven months. The pathology features extensive, fibrillar deposits in frontal, cingulate, and parietal cortex, and in hippocampus.—Hakon Heimer