Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model.

Autor: Latina V; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., De Introna M; Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy.; IRCCS Santa Lucia Foundation (FSL), Centro di Ricerca Europeo sul Cervello (CERC), Via Fosso del Fiorano 64-65, 00143 Rome, Italy., Caligiuri C; IRCCS Santa Lucia Foundation (FSL), Centro di Ricerca Europeo sul Cervello (CERC), Via Fosso del Fiorano 64-65, 00143 Rome, Italy., Loviglio A; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Florio R; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., La Regina F; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Pignataro A; Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy.; IRCCS Santa Lucia Foundation (FSL), Centro di Ricerca Europeo sul Cervello (CERC), Via Fosso del Fiorano 64-65, 00143 Rome, Italy., Ammassari-Teule M; IRCCS Santa Lucia Foundation (FSL), Centro di Ricerca Europeo sul Cervello (CERC), Via Fosso del Fiorano 64-65, 00143 Rome, Italy.; Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Via Ercole Ramarini 32, 00015 Rome, Italy., Calissano P; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Amadoro G; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy.; Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2023 Feb 03; Vol. 15 (2). Date of Electronic Publication: 2023 Feb 03.
DOI: 10.3390/pharmaceutics15020509
Abstrakt: Tau-targeted immunotherapy is a promising approach for treatment of Alzheimer's disease (AD). Beyond cognitive decline, AD features visual deficits consistent with the manifestation of Amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) in the eyes and higher visual centers, both in animal models and affected subjects. We reported that 12A12-a monoclonal cleavage-specific antibody (mAb) which in vivo neutralizes the neurotoxic, N-terminal 20-22 kDa tau fragment(s)-significantly reduces the retinal accumulation in Tg(HuAPP695Swe)2576 mice of both tau and APP/Aβ pathologies correlated with local inflammation and synaptic deterioration. Here, we report the occurrence of N-terminal tau cleavage in the primary visual cortex (V1 area) and the beneficial effect of 12A12mAb treatment on phenotype-associated visuo-spatial deficits in this AD animal model. We found out that non-invasive administration of 12 A12mAb markedly reduced the pathological accumulation of both truncated tau and Aβ in the V1 area, correlated to significant improvement in visual recognition memory performance along with local increase in two direct readouts of cortical synaptic plasticity, including the dendritic spine density and the expression level of activity-regulated cytoskeleton protein Arc/Arg3.1. Translation of these findings to clinical therapeutic interventions could offer an innovative tau-directed opportunity to delay or halt the visual impairments occurring during AD progression.
Databáze: MEDLINE
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