Alzheimer's disease-like neuropathology of gene-targeted APP-SLxPS1mut mice expressing the amyloid precursor protein at endogenous levels.
Most transgenic mice used for preclinical evaluation of potential disease-modifying treatments of Alzheimer's disease develop major histopathological features of this disease by several-fold overexpression of the human amyloid precursor protein. We studied the phenotype of three different strains of gene-targeted mice which express the amyloid precursor protein at endogenous levels. Only further crossing with transgenic mice overexpressing mutant human presenilin1 led to the deposition of extracellular amyloid, accompanied by the deposition of apolipoprotein E, an astrocyte and microglia reaction, and the occurrence of dilated cholinergic terminals in the cortex. Features of neurodegeneration, however, were absent. The pattern of plaque development and deposition in these mice was similar to that of amyloid precursor protein overproducing strains if crossed to presenilin1-transgenics. However, plaque development started much later and developed slowly until the age of 18 months but then increased more rapidly.
Köhler
Christoph
C
Institute II of Anatomy, Department of Neuroanatomy, University of Cologne, Josef Stelzmann-Strasse 9, D-50931 Cologne, Germany. c.koehler@uni-koeln.de
Ebert
Ulrich
U
Baumann
Karlheinz
K
Schröder
Hannsjörg
H
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002678:Chimera; D002799:Cholinergic Fibers / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting / Q000379:methods; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010641:Phenotype; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D002402:Cathepsin D