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Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer ’ s rat model

View Article: PubMed Central - PubMed

ABSTRACT

Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer’s disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.

No MeSH data available.


Effect of intranasal insulin on the brain insulin signaling pathway.(a) Hippocampal homogenates were detected via Western blots. (b) Quantitative analysis was normalized to the GAPDH level. Data are expressed as the means ± SEM (n = 9–11 per group). *P < 0.05 versus the control group; #P < 0.05 versus the STZ/Sal group.
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f6: Effect of intranasal insulin on the brain insulin signaling pathway.(a) Hippocampal homogenates were detected via Western blots. (b) Quantitative analysis was normalized to the GAPDH level. Data are expressed as the means ± SEM (n = 9–11 per group). *P < 0.05 versus the control group; #P < 0.05 versus the STZ/Sal group.

Mentions: To explore the effects of intranasal insulin on brain insulin signaling, we assessed the level and activation of the key components involved, including insulin receptor β-subunit (IRβ), insulin-receptor substrate-1 (IRS1), phosphatidylinositide 3-kinases (PI3K), 3-phosphoinositide-dependent protein kinase-1 (PDK1), and protein kinase B (AKT). The activation of these proteins was assessed by measuring phosphorylation levels at activity-dependent sites. We found that the changes in the total and phosphorylated levels of most proteins were very mild in the hippocampus of ICV-STZ rats compared to control rats (Fig. 6a,b). Consistent with our previous studies1718, the levels of phosphorylated AKT (AKT pT308) were substantially upregulated in ICV-STZ rats (Fig. 6a,b). The levels of IRS1, PI3K p85, and PDK1 in intranasal insulin treated ICV-STZ rats were also markedly stimulated compared to control rats, though these changes were insignificant compared to vehicle treated ICV-STZ rats (Fig. 6a,b). Intranasal insulin treatment restored the levels of AKT pT308 in the hippocampus of ICV-STZ rats (Fig. 6a,b). These results suggest that intranasal insulin treatment modestly boosts brain insulin signaling in the brains of ICV-STZ rats.


Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer ’ s rat model
Effect of intranasal insulin on the brain insulin signaling pathway.(a) Hippocampal homogenates were detected via Western blots. (b) Quantitative analysis was normalized to the GAPDH level. Data are expressed as the means ± SEM (n = 9–11 per group). *P < 0.05 versus the control group; #P < 0.05 versus the STZ/Sal group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382700&req=5

f6: Effect of intranasal insulin on the brain insulin signaling pathway.(a) Hippocampal homogenates were detected via Western blots. (b) Quantitative analysis was normalized to the GAPDH level. Data are expressed as the means ± SEM (n = 9–11 per group). *P < 0.05 versus the control group; #P < 0.05 versus the STZ/Sal group.
Mentions: To explore the effects of intranasal insulin on brain insulin signaling, we assessed the level and activation of the key components involved, including insulin receptor β-subunit (IRβ), insulin-receptor substrate-1 (IRS1), phosphatidylinositide 3-kinases (PI3K), 3-phosphoinositide-dependent protein kinase-1 (PDK1), and protein kinase B (AKT). The activation of these proteins was assessed by measuring phosphorylation levels at activity-dependent sites. We found that the changes in the total and phosphorylated levels of most proteins were very mild in the hippocampus of ICV-STZ rats compared to control rats (Fig. 6a,b). Consistent with our previous studies1718, the levels of phosphorylated AKT (AKT pT308) were substantially upregulated in ICV-STZ rats (Fig. 6a,b). The levels of IRS1, PI3K p85, and PDK1 in intranasal insulin treated ICV-STZ rats were also markedly stimulated compared to control rats, though these changes were insignificant compared to vehicle treated ICV-STZ rats (Fig. 6a,b). Intranasal insulin treatment restored the levels of AKT pT308 in the hippocampus of ICV-STZ rats (Fig. 6a,b). These results suggest that intranasal insulin treatment modestly boosts brain insulin signaling in the brains of ICV-STZ rats.

View Article: PubMed Central - PubMed

ABSTRACT

Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer&rsquo;s disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2&thinsp;U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.

No MeSH data available.