NO-Dependent Akt Inactivation by S-Nitrosylation as a Possible Mechanism of STZ-Induced Neuronal Insulin Resistance

Author(s)

Crunfli, Fernanda ^[1] ; Mazucanti, Caio Henrique ^[2] ; Macedo de Moraes, Ruan Carlos ^[1] ; Costa, Andressa Pereira ^[1] ; Rodrigues, Alice Cristina ^[2] ; Scavone, Cristoforo ^[2] ; Torrao, Andrea da Silva ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, Av Prof Lineu Prestes 1524, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Farmacol, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF ALZHEIMER'S DISEASE; v. 65, n. 4, p. 1427-1443, 2018.
• Web of Science Citations: 2

Abstract

Sporadic Alzheimer's disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-beta activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icy injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD. (AU)

• FAPESP's process: 14/06372-0 - Mechanisms related to neurodegenerative diseases and the involvement of the cannabinoid system
• Grantee: Andréa da Silva Torrão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07427-8 - Aging and neuroprotection: effects of Klotho protein in energetic metabolism, Na,K-ATPase signaling and adaptative response in central nervous system
• Grantee: Cristoforo Scavone
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/14090-3 - Effects of streptozotocin-induced neurodegeneration in neuro2A cells: in vitro model of neurodegeneration associated to Alzheimer's disease
• Grantee: Caio Henrique Yokoyama Mazucanti
• Support Opportunities: Scholarships in Brazil - Master