Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice.
Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aβ pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD×Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD×Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD×Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD×Tg30 than in Tg30 mice. Extracellular amyloid load, Aβ40 and Aβ42, β-CTFs and β-CTF phosphorylation levels were lower in 5xFAD×Tg30 mice than in 5xFAD mice. Despite this reduction of Aβ, a significant hippocampal neuronal loss was observed in 5xFAD×Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD×Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Aβ pathology.
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Céline
C
Héraud
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Doris
D
Goufak
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Kunie
K
Ando
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Karelle
K
Leroy
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Valérie
V
Suain
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Zehra
Z
Yilmaz
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Robert
R
De Decker
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium.
Michèle
M
Authelet
Université Catholique de Louvain (UCL), Institute of Neuroscience, B-1200 Brussels, Belgium.
Vincent
V
Laporte
Université Catholique de Louvain (UCL), Institute of Neuroscience, B-1200 Brussels, Belgium.
Jean-Noël
JN
Octave
Université Libre de Bruxelles (ULB), Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, B-1070 Brussels, Belgium. Electronic address: jpbrion@ulb.ac.be.
Jean-Pierre
JP
Brion
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000648:ultrastructure*; D006624:Hippocampus / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000648:ultrastructure*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D017966:Pyramidal Cells / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins
APP; Alzheimer; Aβ; Neurofibrillary tangles; PS1; Tau; Transgenic