Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult
            <scp>APP</scp>
            swe/
            <scp>PS</scp>
            1dE9 mice

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

doi:10.1111/acel.12498

Cited by 95 publications

(54 citation statements)

References 44 publications

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“…APP/PS1 mice also showed reduced attention to themselves and the environment after evaluation via the open-field test in our study, in agreement with previous studies 27 , and these phenomena were alleviated by Akk treatment. The results of the Y-maze test showed that a high-fat diet further aggravated the impairment of learning and spatial memory ability in APP/PS1 mice.…”

Section: Discussionsupporting

confidence: 93%

“…APPswe/PS1dE9 (APP/PS1) double-transgenic mice and the parasite-free wild-type mice were purchased from the Model Animal Research Center of Nanjing University 27 . In order to clarify whether Akk works only under the conditions of high-fat diet, 3-month-old male APP/PS1 mice were fed ad libitum either a normal chow diet or a high-fat diet (Catalog no.…”

Section: Animal Modelmentioning

confidence: 99%

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Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease

et al. 2020

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Objective: Alzheimer's disease (AD) is a global health problem without effective methods to alleviate the disease progression. Amyloid β-protein (Aβ) is widely accepted as a key biomarker for AD. Metabolic syndromes, including obesity and insulin resistance, are key high risk factors for AD. Akkermansia muciniphila (Akk), the only representative human gut microbe in the genus Verrucomicrobia, can prevent the weight gain caused by a high-fat diet, repair the damaged integrity of the intestinal epithelium barrier, reduce endotoxin levels in blood and improve insulin resistance. The aim of this study is to explore the impact of Akk administration in AD model mice in different diets.Methods: APP/PS1 mice were fed either a normal chow diet or a high-fat diet and were treated with Akk by gavage each day for 6 months. The impacts of Akk on glucose metabolism, intestinal barrier and lipid metabolism in the mouse model of AD were determined. Changes in brain pathology and neuroethology were also analyzed.Results: Akk effectively reduced the fasting blood glucose and serum diamine oxidase levels, and alleviated the reduction of colonic mucus cells in APP/PS1 mice. After treatment with Akk, the APP/PS1 mice showed obviously reduced blood lipid levels, improved hepatic steatosis and scapular brown fat whitening. Moreover, Akk promoted the reduction of Aβ 40-42 levels in the cerebral cortex of APP/PS1 mice, shortened the study time and improved the completion rate in Y-maze tests.Conclusion: Akk effectively improved glucose tolerance, intestine barrier dysfunction and dyslipidemia in AD model mice. Our study results suggested that Akk could delay the pathological changes in the brain and relieve impairment of spatial learning and memory in AD model mice, which provides a new strategy for prevention and treatment of AD.

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Section: Discussionsupporting

confidence: 93%

Section: Animal Modelmentioning

confidence: 99%

Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease

et al. 2020

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“…We found that intranasal insulin elevated the level of DCX in the brain of ICV-STZ rats compared to control rats, which suggested an increase in hippocampal neurogenesis. These results are consistent with our previous reports showing that intranasal insulin can enhance neurogenesis in the hippocampus of APP/PS1 mice50. Synapse loss is an early and invariant feature of AD and correlates well with cognitive decline4551.…”

Section: Discussionsupporting

confidence: 93%

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

Guo

Chen

Mao

et al. 2017

Sci Rep

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108

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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.

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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: 98%

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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Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Cited by 95 publications

References 44 publications

Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease

Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease

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

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

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