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

Guo, Zhangyu; Chen, Yanxing; Mao, Yanfang; Zheng, Tingting; Jiang, Yasi; Yan, Yaping; Yin, Xinzhen; Zhang, Baorong

doi:10.1038/srep45971

Cited by 108 publications

(77 citation statements)

References 57 publications

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“…4E). On the other hand, recent studies showed that intranasal insulin reduces cognitive decline and pathology in AD model animals [76,77]. These data suggest controversial effect of insulin on brain functions.…”

Section: Discussionmentioning

confidence: 99%

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase ( AMPK ), atypical protein kinase C ζ ( aPKC ζ), and insulin receptor substrate 1 ( IRS 1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK , aPKC ζ/λ, and IRS 1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

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Section: Discussionmentioning

confidence: 99%

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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“…29 Glucose and the energy metabolites ATP, ADP, phosphocreatine, and creatine were measured by NMR in homogenized mouse brain tissue following daily doses of 2.4 IU IN insulin for 9 days. Repeated IN insulin administration resulted in increased concentrations of brain glucose [ t (18) = 2.95, p = 0.0086], ATP [ t (17) = 2.21, p = 0.0412], and phosphocreatine [ t (17) = 2.36, p = 0.0304], with a concurrent reduction in creatine [ t (18) = 2.22, p = 0.0393] (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…58 Although preliminary clinical responses are promising, 1,2,8,9,11,29–33 few pharmacokinetic studies have been performed to determine the optimal IN insulin dose or to establish a pharmacokinetic/pharmacodynamic relationship. This is especially important because IN administration of insulin and other peptides is known to result in systemic exposure via absorption through the nasal respiratory epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 The neuroprotective effects of insulin appear to involve the induction or preservation of brain glucose metabolism and restoration of the energy storage molecules adenosine triphosphate (ATP) and phosphocreatine, 13,20–25 in addition to neurotrophic and anti-inflammatory effects mediated by the direct activation of insulin receptors on neurons. 26,27 When delivered to the brain, insulin has been shown to increase glucose uptake 13,18–20,25,28 and improve cognitive performance in animals, 3,7,15,16,25,29 healthy humans, 30–32 and cognitively impaired patients. 1,2,8,9,11,33–37 Given the absence of robust neuroprotective therapeutics, insulin delivery to the brain has thus emerged as a promising new therapy for multiple neurological and psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

Nedelcovych

Gadiano

et al. 2017

ACS Chem. Neurosci.

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Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood–brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUCbrain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUCplasma = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUCbrain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUCplasma = 354 h·μIU/mL), amounting to a ~ 2000-fold increase in the AUCbrain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.

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“…Proteomic analysis also demonstrated that insulin deprivation is accompanied by irreversible PTMs of several proteins that cause t phosphorylation or neurofibrillary degeneration that are pathognomonic of AD. Several reports show t hyperphosphorylation (50)(51)(52) and decreased PP2A activity (50) during insulin deprivation. The current study found that reduced PP2A activity during insulin deficiency can be attributed to irreversible damage to this protein.…”

Section: Discussionmentioning

confidence: 99%

Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes

et al. 2019

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Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin‐induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post‐translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.—Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J. 33, 4458–4472 (2019). http://www.fasebj.org

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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

Cited by 108 publications

References 57 publications

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse

Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes

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