| Autor: |
Latina V; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Giacovazzo G; IRCSS Santa Lucia Foundation, Via Fosso del Fiorano 64-65, 00143 Rome, Italy., Calissano P; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Atlante A; Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM)-CNR, Via Amendola 122/O, 70126 Bari, Italy., La Regina F; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Malerba F; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy., Dell'Aquila M; Area of Pathology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Rome, Italy., Stigliano E; Area of Pathology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Rome, Italy., Balzamino BO; Research Laboratories in Ophthalmology, IRCCS-Fondazione Bietti, Via Santo Stefano Rotondo, 6I, 00184 Rome, Italy., Micera A; Research Laboratories in Ophthalmology, IRCCS-Fondazione Bietti, Via Santo Stefano Rotondo, 6I, 00184 Rome, Italy., Coccurello R; IRCSS Santa Lucia Foundation, Via Fosso del Fiorano 64-65, 00143 Rome, Italy.; Institute for Complex System (ISC)-CNR, Via dei Taurini 19, 00185 Rome, Italy., Amadoro G; European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy.; Institute of Translational Pharmacology (IFT)-CNR, Via Fosso del Cavaliere 100, 00133 Rome, Italy. |
| Abstrakt: |
Tau cleavage plays a crucial role in the onset and progression of Alzheimer's Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)-a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance-mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it's in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity. |
