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 [UCL] Marinangeli, Claudia [UCL] Barbosa de Vasconcelos, Bruno [UCL] Tasiaux, Bernadette [UCL] Laporte, Vincent [UCL] El Haylani, Laetitia [UCL] Pierrot, Nathalie [UCL] Kienlen-Campard, Pascal [UCL] Octave, Jean-Noël [UCL] Dewachter, Ilse [UCL]

Brains of Alzheimer’s Disease (AD) patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, respectively composed of aggregated amyloid peptides and hyperphosphorylated Tau. Several data have indicated beta-amyloid (Abeta) induced aggravation of tau-pathology in in vitro and in vivo models. However, the molecular mechanisms of the communication between Abeta and Tau remain a major black box in the pathogenesis of AD. We here 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. Immunohistochemical data demonstrated a dramatic aggravation of Tau-pathology in mice with combined pathologies. Aggravated Tau-pathology was associated with increased GSK3b-Y216P staining and LC3 and CathepsinD autophagic markers. Longitudinal and spatial immunohistochemical analysis demonstrated that these abnormalities preceded Tau-pathology. Taken together our data further support amyloid-induced Tau-pathology and support a role for dysregulated GSK3b-signaling and autophagy as contributing molecular mechanisms.