Alzheimer's disease-like neuropathology of gene-targeted APP-SLxPS1mut mice expressing the amyloid precursor protein at endogenous levels

• Published in: Neurobiology of disease 2005-11, Vol.20 (2), p.528-540
• Main Authors: Köhler, Christoph, Ebert, Ulrich, Baumann, Karlheinz, Schröder, Hannsjörg
• Format: Article
• Language: English
• Subjects: Alzheimer; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid deposits; Amyloid precursor protein; Animals; Apolipoprotein E; Apolipoproteins E - metabolism; Brain - metabolism; Brain - pathology; Brain - physiopathology; Cathepsin D - metabolism; Cell Line; Chimera; Choline acetyltransferase; Cholinergic Fibers - metabolism; Cholinergic Fibers - pathology; Disease Models, Animal; Female; Gene Targeting - methods; Gene-targeted; Gliosis - genetics; Gliosis - metabolism; Gliosis - physiopathology; Humans; Immunohistochemistry; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Mutant Strains; Mice, Transgenic; Microglia; Phenotype; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Presenilin-1; Presynaptic Terminals - metabolism; Presynaptic Terminals - pathology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2005.04.009

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.