YAC transgenic model of Alzheimer disease

Abstract

Chromosome 21 dosage imbalances in Down syndrome and mutations in the amyloid precursor protein (APP) and presenilin 1 (PS 1) genes in early-onset familial Alzheimer disease (FAD) result in the increased production and deposition of amyloid β (Aβ) peptides, particularly of the 42 amino acid form. Many transgenic mice have been produced using cDNA-based expression of APP or PS-1 gene fragments. However, yeast artificial chromosome (YAC) transgenesis allows for the incorporation of genomic sequences that contain all the transcriptional regulatory elements necessary for proper spatial and temporal expression, with the appropriate splice-donor and acceptor sites required to generate the entire spectrum of alternatively spliced transcripts and protein isoforms of APP and PS-1. Thus, YAC transgenic approaches might provide unique insights into mechanism(s) and progression of AD in humans.Lamb et al.1xAmyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome mice. Lamb, B.T. et al. Nat. Neurosci. 1999; 2: 695–697Crossref | PubMed | Scopus (87)See all References1 examined the effects of FAD mutations in vivo by transferring 1 000 kb YACs, containing the entire genomic copy of human APP and/or PS-1 genes harboring FAD mutations, into mouse embryonic stem cells to generate YAC transgenic mice. They report that mutant APP YAC transgenic mice develop Aβ deposits in the frontal cortex and the hippocampus, which is the same location observed in FAD patients. This deposition is accelerated when the animals are mated to homozygosity and/or to mutant PS-1 YAC transgenic mice. Interestingly, no mention has been made by the authors about the phenotype of these mice. The relationship of Aβ deposits in transgenic mice with respect to dementia, neurofibrillary tangles, neuron loss and other phenotypes associated with AD still, therefore, remains unclear.