Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Neurobiology of Disease Année : 2024

Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice

Geoffrey Canet
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Charleine Zussy
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Mohamed Lala Bouali
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Emma Rocaboy
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Francis Laliberté
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Cyntia Tremblay
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Françoise Morin
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Frédéric Calon
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Sébastien S Hébert
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Carl Julien
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Emmanuel Planel
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Résumé

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is a widely used rodent model to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology. STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-β (Aβ) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might facilitate a direct neurotoxic effect of STZ in older mice. Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.
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hal-04587597 , version 1 (24-05-2024)

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Geoffrey Canet, Maud Gratuze, Charleine Zussy, Mohamed Lala Bouali, Sofia Diego Diaz, et al.. Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice. Neurobiology of Disease, In press, pp.106526. ⟨10.1016/j.nbd.2024.106526⟩. ⟨hal-04587597⟩
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