Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
| Autor: | Francesca Malerba, Roberto Coccurello, Pietro Calissano, Egidio Stigliano, Bijorn Omar Balzamino, Giuseppina Amadoro, Anna Atlante, Marco Dell'Aquila, Giacomo Giacovazzo, Alessandra Micera, Federico La Regina, Valentina Latina |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_treatment medicine.disease_cause neuroinflammation Pathogenesis Mice Amyloid precursor protein oxidative stress Biology (General) Spectroscopy cognitive/memory impairment biology General Medicine streptozotocin (STZ) Computer Science Applications Chemistry non-transgenic Alzheimer’s Disease mouse model immunotherapy tau cleavage medicine.drug medicine.medical_specialty QH301-705.5 Mice Transgenic tau Proteins Neuroprotection Streptozocin Article Catalysis Inorganic Chemistry Alzheimer Disease Internal medicine mental disorders medicine Animals Cognitive Dysfunction Physical and Theoretical Chemistry Molecular Biology Protein kinase B QD1-999 Neuroinflammation business.industry Insulin Organic Chemistry Streptozotocin Endocrinology Proteolysis biology.protein non-transgenic Alzheimer's Disease mouse model business Oxidative stress |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 12158, p 12158 (2021) International Journal of Molecular Sciences Volume 22 Issue 22 International journal of molecular sciences 22 (2021): 12158-1–12158-35. doi:10.3390/ijms222212158 info:cnr-pdr/source/autori:Latina V.; Giacovazzo G.; Calissano P.; Atlante A.; La Regina F.; Malerba F.; Dell'aquila M.; Stigliano E.; Balzamino B.O.; Micera A.; Coccurello R.; Amadoro G./titolo:Tau cleavage contributes to cognitive dysfunction in strepto-zotocin-induced sporadic alzheimer's disease (Sad) mouse model/doi:10.3390%2Fijms222212158/rivista:International journal of molecular sciences (Print)/anno:2021/pagina_da:12158-1/pagina_a:12158-35/intervallo_pagine:12158-1–12158-35/volume:22 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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