Neurodegenerative Changes Associated with β-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 β-amyloid (Aβ) production. Despite the fact that a number of transgenic mice develop cerebral Aβ plaques, few have been subjected to ultrastructural investigation and the sequence of events leading to Aβ plaqu...

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Bibliographic Details
Published in:	Experimental neurology Vol. 171; no. 1; pp. 59 - 71
Main Authors:	Kurt, M.A., Davies, D.C., Kidd, M., Duff, K., Rolph, S.C., Jennings, K.H., Howlett, D.R.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Inc 01-09-2001 Elsevier
Subjects:	Aging - metabolism Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - ultrastructure Amyloid beta-Protein Precursor - genetics Animals Biological and medical sciences Brain - metabolism Brain - pathology Brain - ultrastructure Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Immunohistochemistry Medical sciences Membrane Proteins - genetics Mice Mice, Transgenic Microscopy, Immunoelectron Mutation Neurodegenerative Diseases - genetics Neurodegenerative Diseases - pathology Neurology Plaque, Amyloid - pathology Plaque, Amyloid - ultrastructure Presenilin-1 Transgenes Nervous system diseases Alzheimer disease Rodentia Transgenic animal Presenilin White matter Amyloid precursor protein Cerebral disorder Microglia Vertebrata Mammalia Oligodendrocyte Mouse β Amyloid protein Central nervous system disease Degenerative disease Amyloid Mutation
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Summary:	Mutations of amyloid precursor protein (APP) and presenilin-1 (PS1) lead to an increase in β-amyloid (Aβ) production. Despite the fact that a number of transgenic mice develop cerebral Aβ plaques, few have been subjected to ultrastructural investigation and the sequence of events leading to Aβ plaque formation is unclear. We therefore investigated the doubly transgenic (mutant APPK670N,M671L–mutant PS1M146L) mouse, which develops Aβ deposits much earlier than singly transgenic littermates. Widespread Aβ plaques with or without a distinct core were found in gray matter. Aβ plaques were also present in white matter. Astrocytosis was greater around gray matter plaques than around white matter plaques. In some plaques, Aβ cores were associated with cell profiles containing prominent endoplasmic reticulum and a homogenous cytoplasm that appeared to be neuronal. The morphology and location of other profiles indicated them to be microglia or oligodendrocytes. Some Aβ 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 Aβ 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-4886 1090-2430
DOI:	10.1006/exnr.2001.7717