No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the β-cleaved C-terminal APP fragment

• Published in: Neurobiology of disease 2003-03, Vol.12 (2), p.110-120
• Main Authors: Rutten, Bart P.F, Wirths, Oliver, Van de Berg, Wilma D.J, Lichtenthaler, Stefan F, Vehoff, Jochen, Steinbusch, Harry W.M, Korr, Hubert, Beyreuther, Konrad, Multhaup, Gerd, Bayer, Thomas A, Schmitz, Christoph
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - metabolism; Animals; Cell Death - genetics; Disease Models, Animal; Gene Expression Regulation - genetics; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; Immunohistochemistry; Intraneuronal Aβ; Mice; Mice, Transgenic; Mutation - genetics; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurodegeneration; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Presynaptic Terminals - metabolism; Presynaptic Terminals - pathology; Protein Structure, Tertiary - genetics; SPA4CT; Stereology; Synaptophysin; Synaptophysin - metabolism; Transgenes - genetics; Transgenic; Western blot
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/S0969-9961(02)00015-3

Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the β-cleaved Alzheimer’s disease C-terminal fragment (β-CTF) of β-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human β-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 β-CTF released Aβ. 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 β-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer’s disease brain.