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 (Abeta) production. Despite the fact that a number of transgenic mice develop cerebral Abeta plaques, few have been subjected to ultrastructural investigation and the sequence of events leading to Abeta plaque formation is unclear. We therefore investigated the doubly transgenic (mutant APP(K670N,M671L)-mutant PS1(M146L)) mouse, which develops Abeta deposits much earlier than singly transgenic littermates. Widespread Abeta plaques with or without a distinct core were found in gray matter. Abeta plaques were also present in white matter. Astrocytosis was greater around gray matter plaques than around white matter plaques. In some plaques, Abeta cores were associated with cell profiles containing prominent endoplasmic reticulum and a homogeneous cytoplasm that appeared to be neuronal. The morphology and location of other profiles indicated them to be microglia or oligodendrocytes. Some Abeta fibrils appeared to lie within these profiles, but they may have been simply surrounded by the cell profile since the profile membrane was not always visible. Dark atrophic neurons, whose morphology suggested that they were apoptotic, were present around gray matter plaques. Cerebrovascular Abeta deposition was also observed in the brains of APP/PS1 transgenic mice. Thus, the amyloid deposition and neuropathology observed in APP/PS1 mouse brain are similar to those in Alzheimer's disease and they appear to develop earlier and become more severe than in the other transgenic models currently available.
Kurt
M A
MA
St George's Hospital Medical School, London, United Kingdom.
Davies
D C
DC
Kidd
M
M
Duff
K
K
Rolph
S C
SC
Jennings
K H
KH
Howlett
D R
DR
D000375:Aging / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D058225:Plaque, Amyloid / Q000473:pathology / Q000648:ultrastructure; D053764:Presenilin-1; D019076:Transgenes
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1