title: No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment.
abstract: Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the beta-cleaved Alzheimer's disease C-terminal fragment (beta-CTF) of beta-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human beta-CTF with the I45F mutation (SPA4CT) under control of the prion protein promoter by stereological techniques. The transgene was expressed in hippocampus and cortex in large pyramidal neurons and in dentate gyrus granule cells. Proteolytic processing of beta-CTF released Abeta. However, most of it remained uncleaved. Neurodegeneration was evaluated by investigating the numbers of hippocampal pyramidal and granule neurons, as well as the number of synaptophysin-immunopositive presynaptic boutons in the hippocampus of 15-month-old SPA4CT mice with design-based stereological techniques. The analyses showed that a fourfold higher expression of the transgene compared to murine APP levels had no effect on the numbers of both neurons and synaptophysin-immunopositive presynaptic boutons. These data implicate that expression of beta-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer's disease brain.
authors.affiliation: Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.forename: Wilma D J
authors.initials: WD
authors.lastname: Van de Berg
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: Jochen
authors.initials: J
authors.lastname: Vehoff
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Hubert
authors.initials: H
authors.lastname: Korr
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmitz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D016708:Synaptophysin