No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the β-cleaved C-terminal APP fragment
Copyright policy )No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the β-cleaved C-terminal APP fragment
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.
- RWTH Aachen University Germany
- Maastricht University Netherlands
- European Graduate School Switzerland
- Amsterdam UMC, location VUmc Netherlands
- Massachusetts General Hospital United States
Protein Structure, Mutation/genetics, Transgenes/genetics, Amyloid beta-Peptides/biosynthesis, Stereology, Hippocampus/metabolism, Presynaptic Terminals, Synaptophysin, Neurosciences. Biological psychiatry. Neuropsychiatry, Mice, Transgenic, Synaptophysin/metabolism, Cell Death/genetics, Tertiary/genetics, Gene Expression Regulation/genetics, Hippocampus, Transgenic, Nerve Degeneration/genetics, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, SPA4CT, Animals, Transgenes, Peptide Fragments/genetics, Neurodegeneration, Alzheimer Disease/genetics, Amyloid beta-Peptides, Cell Death, Animal, Intraneuronal Aβ, Amyloid beta-Protein Precursor/metabolism, Immunohistochemistry, Peptide Fragments, Protein Structure, Tertiary, Presynaptic Terminals/metabolism, Disease Models, Animal, Gene Expression Regulation, Disease Models, Mutation, Nerve Degeneration, RC321-571
Protein Structure, Mutation/genetics, Transgenes/genetics, Amyloid beta-Peptides/biosynthesis, Stereology, Hippocampus/metabolism, Presynaptic Terminals, Synaptophysin, Neurosciences. Biological psychiatry. Neuropsychiatry, Mice, Transgenic, Synaptophysin/metabolism, Cell Death/genetics, Tertiary/genetics, Gene Expression Regulation/genetics, Hippocampus, Transgenic, Nerve Degeneration/genetics, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, SPA4CT, Animals, Transgenes, Peptide Fragments/genetics, Neurodegeneration, Alzheimer Disease/genetics, Amyloid beta-Peptides, Cell Death, Animal, Intraneuronal Aβ, Amyloid beta-Protein Precursor/metabolism, Immunohistochemistry, Peptide Fragments, Protein Structure, Tertiary, Presynaptic Terminals/metabolism, Disease Models, Animal, Gene Expression Regulation, Disease Models, Mutation, Nerve Degeneration, RC321-571
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