Article
The impact of amyloid β-protein aggregation and production on tau pathology in different APP-TAU double transgenic mouse models
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Authors
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Silvia Hipp
- Laboratory of Neuropathology - Institute of Pathology, Center for Clinical Research at the University of Ulm, Ulm, Germany
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Ajeet Rijal Upadhaya
- Laboratory of Neuropathology - Institute of Pathology, Center for Clinical Research at the University of Ulm, Ulm, Germany
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Irina Kosterin
- Laboratory of Neuropathology - Institute of Pathology, Center for Clinical Research at the University of Ulm, Ulm, Germany
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Marcus Fändrich
- Max Planck Research Unit for Enzymology of Protein Folding and Martin-Luther University Halle-Wittenberg, Halle, Germany
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Sabine Rabe
- Novartis Institutes for Biochemical Research, Basel, Switzerland
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Matthias Staufenbiel
- Novartis Institutes for Biochemical Research, Basel, Switzerland
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Dietmar Rudolf Thal
- Laboratory of Neuropathology - Institute of Pathology, Center for Clinical Research at the University of Ulm, Ulm, Germany
| Published: | September 11, 2012 |
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Outline
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Deposition of amyloid β protein (Aβ) in senile plaques and formation of neurofibrillary tangles (NFTs) consisting of abnormal phosphorylated tau-protein in the brain are histopathological hallmarks of Alzheimer's disease (AD). The possible link between Aβ and tau pathology has not been clarified in detail so far. The APP48 mouse expresses Aβ 1-42 on the luminal membrane side and shows only intracellular Aβ-lesions. APP23 mice overexpress human APP with the swedish mutation, APP51/16 mice overexpress human wildtype APP, and both mouse strains develop Aβ plaques. APP23 mice, thereby, show neurodegeneration but APP51/16 mice do not. To clarify possible links between tau pathology and intra- and/or extracellular Aβ aggregation, the three mouse models were crossbreed with mutated tau (P301S)-transgenic mice (TAU58/2).
Immunoprecipitation with A11 and B10AP antibodies/ antibody fragments from the dispersible fraction of the brain homogenates and subsequent western blot analysis demonstrated that the levels of Aβ protofibrils and fibrils precipitated with B10AP and high molecular weight oligomers precipitated with A11 are higher in APP23xTAU58/2 mice compared to APP51/16xTAU58/2 mice. APP48xTAU58/2 mice show slightly lower levels of dispersible Aβ compared to APP23xTAU58/2 mice but no soluble Aβ which is seen in APP23xTAU58/2 and APP51/16xTAU58/2 mice. Immunohistochemistry with an antibody against abnormally phosporylated tau-protein revealed more serve tau pathology in APP23xTAU58/2 mice than in TAU58/2 single transgenic mice whereas APP51/16xTAU58/2 and APP48xTAU58/2 mice did not exhibit significantly different levels of tau pathology compared to TAU58/2 single transgenic animals.
These results show that the quantity of dispersible Aβ seems to be critical for accelerating tau pathology. Moreover, comparison between APP23xTAU58/2 and APP48xTAU58/2 mice suggests that the subcellular compartment, in which Aβ is generated, plays an important role for possible toxic interactions with tau. Although the levels of dispersible Aβ are similar in APP48xTAU58/2 and APP23xTAU58/2 mice the intracellular location in APP48xTAU58/2 does not support the acceleration of tau pathology.
Supported by Alzheimer Forschung Initiative Grant No.: #10810.
