Limits...
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 neuroinflammation markers.(a) The GFAP and Iba1 levels in whole hippocampus extracts were measured via Western blots. (b) Densitometric quantification of the blots after normalization 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. (c) Representative immunohistochemical staining of brain sections with an antibody against Iba1, n = 4 per group. Scale bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382700&req=5

f4: Effect of intranasal insulin on neuroinflammation markers.(a) The GFAP and Iba1 levels in whole hippocampus extracts were measured via Western blots. (b) Densitometric quantification of the blots after normalization 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. (c) Representative immunohistochemical staining of brain sections with an antibody against Iba1, n = 4 per group. Scale bar = 50 μm.

Mentions: Neuroinflammation, as reflected by astrogliosis and microglial activation, is a pathological hallmark of AD that precedes plaque and tangle formation during AD progression2627. The activation of astrocytes and microglia is also observed in ICV-STZ treated animals1728. To investigate the effects of intranasal insulin on neuroinflammation in the hippocampus of ICV-STZ rats, we measured the level of glial fibrillary acidic protein (GFAP), the commonly used marker for astrocytes, and ionized Ca2+-binding adaptor molecule-1 (Iba1), a marker of microglia, via Western blots. Consistent with our previous findings, we observed a substantial increase in the level of GFAP and Iba1 in the hippocampus of ICV-STZ rats compared to control rats (Fig. 4a,b). Furthermore, the level of Ibal was markedly suppressed in intranasal insulin treated ICV-STZ rats than in vehicle treated rats. Immunohistochemical staining for Iba1 confirmed the over-activation of microglia in the hippocampus of the ICV-STZ rats, which was also ameliorated by treatment with intranasal insulin (Fig. 4c).


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 neuroinflammation markers.(a) The GFAP and Iba1 levels in whole hippocampus extracts were measured via Western blots. (b) Densitometric quantification of the blots after normalization 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. (c) Representative immunohistochemical staining of brain sections with an antibody against Iba1, n = 4 per group. Scale bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Effect of intranasal insulin on neuroinflammation markers.(a) The GFAP and Iba1 levels in whole hippocampus extracts were measured via Western blots. (b) Densitometric quantification of the blots after normalization 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. (c) Representative immunohistochemical staining of brain sections with an antibody against Iba1, n = 4 per group. Scale bar = 50 μm.
Mentions: Neuroinflammation, as reflected by astrogliosis and microglial activation, is a pathological hallmark of AD that precedes plaque and tangle formation during AD progression2627. The activation of astrocytes and microglia is also observed in ICV-STZ treated animals1728. To investigate the effects of intranasal insulin on neuroinflammation in the hippocampus of ICV-STZ rats, we measured the level of glial fibrillary acidic protein (GFAP), the commonly used marker for astrocytes, and ionized Ca2+-binding adaptor molecule-1 (Iba1), a marker of microglia, via Western blots. Consistent with our previous findings, we observed a substantial increase in the level of GFAP and Iba1 in the hippocampus of ICV-STZ rats compared to control rats (Fig. 4a,b). Furthermore, the level of Ibal was markedly suppressed in intranasal insulin treated ICV-STZ rats than in vehicle treated rats. Immunohistochemical staining for Iba1 confirmed the over-activation of microglia in the hippocampus of the ICV-STZ rats, which was also ameliorated by treatment with intranasal insulin (Fig. 4c).

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.