Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse

Doubly transgenic mice expressing both a mutated amyloid precursor protein and a mutated presenilin-1 protein accumulate Abeta deposits as they age. The early Abeta deposits were found to be primarily composed of fibrillar Abeta and resembled compact amyloid plaques. As the mice aged, nonfibrillar Abeta deposits increased in number and spread to regions not typically associated with amyloid plaques in Alzheimer's disease. e fibrillar, amyloid-containing deposits remained restricted to cortical and hippocampal structures and did not increase substantially beyond the 12-month time point. Even at early time points, the fibrillar deposits were associated with dystrophic neurites and activated astrocytes expressing elevated levels of glial fibrillary acidic protein. Microglia similarly demonstrated increased staining for complement receptor-3 in the vicinity of Abeta deposits at early time points. However, when MHC-II staining was used to assess the degree of microglial activation, full activation was not detected until mice were 12 months or older. Overall, the regional pattern of Abeta staining resembles that found in Alzheimer disease; however, a progression from diffuse Abeta to more compact amyloid deposits is not observed in the mouse model. It is noted that the activation of microglia at 12 months is coincident with the apparent stabilization of fibrillar Abeta deposits, raising the possibility that activated microglia might clear fibrillar Abeta deposits at a rate similar to their rate of formation, thereby establishing a relatively steady-state level of amyloid-containing deposits. (C) 2001 Elsevier Science (USA).