Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes

Mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) lead to an increase in beta -amyloid (A beta) production. Despite the fact that a number of transgenic mice develop cerebral A beta plaques, few have been su bjected to ultrastructural investigation and the sequence of events leading to A beta plaque formation is unclear. We therefore investigated the doubl y transgenic (mutant APP(K670N,M671L)-mutant PS1(M146L)) mouse, which devel ops A beta deposits much earlier than singly transgenic littermates. Widesp read A beta plaques with or without a distinct core were found in gray matt er. A beta plaques were also present in white matter. Astrocytosis was grea ter around gray matter plaques than around white matter plaques. In some pl aques, A beta cores were associated with cell profiles containing prominent endoplasmic reticulum and a homogenous cytoplasm that appeared to be neuro nal. The morphology and location of other profiles indicated them to be mic roglia or oligodendrocytes. Some A beta fibrils appeared to lie within thes e profiles, but they may have been simply surrounded by the cell profile si nce the profile membrane was not always visible. Dark atrophic neurons, who se morphology suggested that they were apoptotic, were present around gray matter plaques. Cerebrovascular A beta deposition was also observed in the brains of A-PP/PS1 transgenic mice. Thus, the amyloid deposition and neurop athology observed in A-PP/PS1 mouse brain are similar to those in Alzheimer 's disease and they appear to develop earlier and become more severe than i n the other transgenic models currently available. (C) 2001 Academic Press.