Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer’s disease models

• DOI: 10.1093/braincomms/fcaa039
• Publication Date: 2020-04-06T17:06:06Z
• Authors: Veronica Corsetti; Antonella Borreca; Valentina Latina; Giacomo Giacovazzo; Annabella Pignataro; Paraskevi Krashia; Francesca Natale; Sara Cocco; Marco Rinaudo; Francesca Malerba; Rita Florio; Roberta Ciarapica; Roberto Coccurello; Marcello D’Amelio; Martine Ammassari...; Claudio Grassi; Pietro Calissano; Giuseppina Amadoro
• Keywords: Tau protein; Cognitive Decline

Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making an attractive target for cure Alzheimer's disease. We explored whether passive immunization 12A12 monoclonal antibody (26-36aa protein) could improve disease phenotype two well-established mouse models, Tg2576 3xTg mice. is a cleavage-specific which selectively binds pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) protein without cross-reacting its full-length physiological form(s). found out intravenous administration into symptomatic (6 months old) animals: (i) reaches hippocampus in biologically active (antigen-binding competent) form successfully neutralizes target; (ii) reduces both pathological precursor protein/amyloidβ metabolisms involved early disease-associated synaptic deterioration; (iii) improves episodic-like type learning/memory skills hippocampal-based novel object recognition place behavioural tasks; (iv) restores specific up-regulation activity-regulated cytoskeleton-associated consolidation experience-dependent plasticity; (v) relieves loss dendritic spine connectivity pyramidal hippocampal CA1 neurons; (vi) rescues disease-related electrophysiological deficits long-term potentiation at CA3-CA1 synapses; (vii) mitigates neuroinflammatory response (reactive gliosis). These findings indicate 20-22 kDa NH2-terminal crucial therapy prospect immunotherapy as safe (normal tau-preserving), beneficial approach contrasting Amyloidβ-dependent independent cognitive alterations affected subjects.