Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation

Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the gen eration of A beta 1-42, indicating that PS-1 is involved in amyloidogenesis . However, PS-l transgenic mice have failed to show amyloid plaques in thei r brains. Because PS-l mutations facilitate apoptotic neuronal death in vit ro, we did careful quantitative studies in PS-1 transgenic mice and found t hat neurodegeneration was significantly accelerated in mice older than 13 m onths (aged mice) with familial Alzheimer disease mutant PS-1, without amyl oid plaque formation. However, there were significantly more neurons contai ning intracellularly deposited A beta 42 in aged mutant transgenic mice. Ou r data indicate that the pathogenic role of the PS-1 mutation is upstream o f the amyloid cascade.