Aggravated Tau-pathology in a novel mouse model with combined amyloid and Tau-pathology is preceded by dysregulated GSK3b signaling and autophagy

Stancu, Ilie-Cosmin;Marinangeli, Claudia;Barbosa de Vasconcelos, Bruno;Tasiaux, Bernadette;Dewachter, Ilse;et.al.
(2013) The 11th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD 2013) — Location: Florence, Italy (6.March.2013)

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  • Stancu, Ilie-CosminUCLouvain
    Author
  • Marinangeli, ClaudiaUCLouvain
    Author
  • Barbosa de Vasconcelos, BrunoUCLouvain
    Author
  • Tasiaux, BernadetteUCLouvain
    Author
  • Dehalleux, CélineUCLouvain
    Author
  • Laporte, VincentUCLouvain
    Author
  • El Haylani, LaetitiaUCLouvain
    Author
  • Pierrot, NathalieUCLouvain
    Author
  • Kienlen-Campard, Pascalorcid-logoUCLouvain
    Author
  • Octave, Jean-NoëlUCLouvain
    Author
  • Dewachter, IlseUCLouvain
    Author
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Abstract
Objectives: Amyloid plaques and neurofibrillary tangles represent the diagnostic hallmarks of AD. Several data have indicated beta-amyloid induced aggravation of tau-pathology in vitro and in vivo. However, the molecular mechanisms of the communication between ABeta and Tau remain a major black box in the pathogenesis of AD. We here aimed at the generation of a novel model with combined amyloid and tau-pathology to study the link between both. The analysis of different models, varying in degree, region and type of amyloid (intra- and extra-cellular) pathology is important to uncage different aspects of this link. Methods: We have crossbred 5xFAD transgenic mice with TauP301S transgenic mice, to generate mice with combined amyloid and tau-pathology, further denoted F+/T+. Comparative immunohistochemical analysis of F+/T+ transgenic mice and F+/T- and F-/T+ parental strains was performed at 3, 6 and 9 months of age for intraneuronal and plaque-associated ABeta, P-Tau, NFTs, GSK3b, LC3 and CathepsinD. Results: Immunohistochemical analysis demonstrated a dramatic aggravation of Tau-pathology in F+/T+ mice compared to F-/T+ mice. Aggravated Tau-pathology was associated with increased GSK3b-Y216P staining and changes in LC3 and CathepsinD autophagic markers. Longitudinal and spatial immunohistochemical analysis demonstrated that these abnormalities preceded Tau-pathology. Conclusions: We have generated a novel model with robust combined amyloid and tau-pathology, providing a preclinical model to evaluate therapeutic targets for their combined and specific modulatory effects on amyloid and tau-pathology. Furthermore, our data demonstrate a dramatic amyloid-induced Tau-pathology and support a role for dysregulated GSK3b-signaling and autophagy as contributing mechanisms.
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Stancu, I.-C., Marinangeli, C., Barbosa de Vasconcelos, B., Tasiaux, B., Dehalleux, C., Laporte, V., El Haylani, L., Pierrot, N., Kienlen-Campard, P., Octave, J.-N., & Dewachter, I. (2013). Aggravated Tau-pathology in a novel mouse model with combined amyloid and Tau-pathology is preceded by dysregulated GSK3b signaling and autophagy. The 11th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD 2013), Florence, Italy. https://hdl.handle.net/2078.5/185022