Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

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...

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Autores principales:	Valentina Latina, Giacomo Giacovazzo, Pietro Calissano, Anna Atlante, Federico La Regina, Francesca Malerba, Marco Dell’Aquila, Egidio Stigliano, Bijorn Omar Balzamino, Alessandra Micera, Roberto Coccurello, Giuseppina Amadoro
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tau cleavage non-transgenic Alzheimer’s Disease mouse model streptozotocin (STZ) immunotherapy cognitive/memory impairment neuroinflammation Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/5f991db7a1c14822a963b16909db6ad5
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spelling	oai:doaj.org-article:5f991db7a1c14822a963b16909db6ad52021-11-25T17:53:51ZTau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model10.3390/ijms2222121581422-00671661-6596https://doaj.org/article/5f991db7a1c14822a963b16909db6ad52021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12158https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Tau 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.Valentina LatinaGiacomo GiacovazzoPietro CalissanoAnna AtlanteFederico La ReginaFrancesca MalerbaMarco Dell’AquilaEgidio StiglianoBijorn Omar BalzaminoAlessandra MiceraRoberto CoccurelloGiuseppina AmadoroMDPI AGarticletau cleavagenon-transgenic Alzheimer’s Disease mouse modelstreptozotocin (STZ)immunotherapycognitive/memory impairmentneuroinflammationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12158, p 12158 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tau cleavage non-transgenic Alzheimer’s Disease mouse model streptozotocin (STZ) immunotherapy cognitive/memory impairment neuroinflammation Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	tau cleavage non-transgenic Alzheimer’s Disease mouse model streptozotocin (STZ) immunotherapy cognitive/memory impairment neuroinflammation Biology (General) QH301-705.5 Chemistry QD1-999 Valentina Latina Giacomo Giacovazzo Pietro Calissano Anna Atlante Federico La Regina Francesca Malerba Marco Dell’Aquila Egidio Stigliano Bijorn Omar Balzamino Alessandra Micera Roberto Coccurello Giuseppina Amadoro Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
description	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.
format	article
author	Valentina Latina Giacomo Giacovazzo Pietro Calissano Anna Atlante Federico La Regina Francesca Malerba Marco Dell’Aquila Egidio Stigliano Bijorn Omar Balzamino Alessandra Micera Roberto Coccurello Giuseppina Amadoro
author_facet	Valentina Latina Giacomo Giacovazzo Pietro Calissano Anna Atlante Federico La Regina Francesca Malerba Marco Dell’Aquila Egidio Stigliano Bijorn Omar Balzamino Alessandra Micera Roberto Coccurello Giuseppina Amadoro
author_sort	Valentina Latina
title	Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
title_short	Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
title_full	Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
title_fullStr	Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
title_full_unstemmed	Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model
title_sort	tau cleavage contributes to cognitive dysfunction in strepto-zotocin-induced sporadic alzheimer’s disease (sad) mouse model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5f991db7a1c14822a963b16909db6ad5
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Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

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