TY - JOUR
T1 - No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment
AU - Rutten, Bart P F
AU - Wirths, Oliver
AU - Van de Berg, Wilma D J
AU - Lichtenthaler, Stefan F
AU - Vehoff, Jochen
AU - Steinbusch, Harry W M
AU - Korr, Hubert
AU - Beyreuther, Konrad
AU - Multhaup, Gerd
AU - Bayer, Thomas A
AU - Schmitz, Christoph
N1 - Copyright 2003 Elsevier Science (USA)
PY - 2003/3
Y1 - 2003/3
N2 - 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.
AB - 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.
KW - Alzheimer Disease/genetics
KW - Amyloid beta-Peptides/biosynthesis
KW - Amyloid beta-Protein Precursor/metabolism
KW - Animals
KW - Cell Death/genetics
KW - Disease Models, Animal
KW - Gene Expression Regulation/genetics
KW - Hippocampus/metabolism
KW - Immunohistochemistry
KW - Mice
KW - Mice, Transgenic
KW - Mutation/genetics
KW - Nerve Degeneration/genetics
KW - Peptide Fragments/genetics
KW - Presynaptic Terminals/metabolism
KW - Protein Structure, Tertiary/genetics
KW - Synaptophysin/metabolism
KW - Transgenes/genetics
M3 - Article
C2 - 12667466
VL - 12
SP - 110
EP - 120
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 2
ER -