New insights concerning insulin synthesis and its secretion in rat hippocampus and cerebral cortex: Amyloid-β1–42-induced reduction of proinsulin level via glycogen synthase kinase-3β

Nemoto, Takayuki; Toyoshima-Aoyama, Fumiyo; Yanagita, Toshihiko; Maruta, Toyoaki; Fujita, Hiroshi; Koshida, Tomohiro; Yonaha, Tetsu; Wada, Akihiko; Sawaguchi, Akira; Murakami, Manabu

doi:10.1016/j.cellsig.2013.11.017

Cited by 29 publications

(20 citation statements)

References 34 publications

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“…Once taken up by the β cells, the N -methyl- N -nitrosurea moiety of STZ exerts its cytotoxic effects leading to cell death, and thus loss of pancreatic insulin secretion [26]. In the brain, however, GLUT2 is expressed at relatively low levels by few, if any, neurons expressing insulin, especially pyramidal neurons of the neocortex and hippocampus (CA1-3) [27–29]. This may explain why ICV STZ has not been shown to affect protein levels of brain insulin [30] and why this drug treatment has inconsistent effects on gene and/or protein expression of upstream versus downstream insulin signaling molecules within and across brain structures [31–33].…”

Section: Discovery Of Brain Insulin Resistance In Admentioning

confidence: 99%

“…Its classic functions are stimulation of glucose uptake by adipose and muscle tissue and inhibition of no longer needed free fatty acid release by adipose tissue and glucose production by the liver. However, insulin is also synthesized in brain neurons [64], including many pyramidal and granule cells in adult cerebral cortex and hippocampus [28,29], where the density of insulin receptors is appreciable [65]. Although pancreatic insulin is transported in small amounts across the blood–brain barrier in many brain regions and exerts effects on brain function, especially in the hypothalamus [66], most insulin in the brain outside the hypothalamus seems locally derived because vascular hypo- and hyperinsulinemia has little, if any, effect on total brain insulin [67].…”

Section: Significance Of Brain Insulin Resistance In Admentioning

confidence: 99%

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The nature, significance, and glucagon‐like peptide‐1 analog treatment of brain insulin resistance in Alzheimer's disease

Talbot¹,

Wang

2014

Alzheimer's & Dementia

108

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease leading over the course of decades to the most common form of dementia. Many of its pathologic features and cognitive deficits may be due in part to brain insulin resistance recently demonstrated in the insulin receptor→insulin receptor substrate-1 (IRS-1) signaling pathway. The proximal cause of such resistance in AD dementia and amnestic mild cognitive impairment (aMCI) appears to be serine inhibition of IRS-1, a phenomenon likely due to microglial release of inflammatory cytokines triggered by oligomeric Aβ. Studies on animal models of AD and on human brain tissue from MCI cases at high risk of AD dementia have shown that brain insulin resistance and many other pathologic features and symptoms of AD may be greatly reduced or even reversed by treatment with FDA-approved glucagon-like peptide-1 (GLP-1) analogs such as liraglutide (Victoza). These findings call attention to the need for further basic, translational, and clinical studies on GLP-1 analogs as promising AD therapeutics.

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Section: Discovery Of Brain Insulin Resistance In Admentioning

confidence: 99%

Section: Significance Of Brain Insulin Resistance In Admentioning

confidence: 99%

The nature, significance, and glucagon‐like peptide‐1 analog treatment of brain insulin resistance in Alzheimer's disease

Talbot¹,

Wang

2014

Alzheimer's & Dementia

108

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“…A potential autocrine/paracrine effect of insulin/proinsulin in the brain has been suspected for some time, because moderate insulin/proinsulin levels were found in the brain independently of peripheral levels (Havrankova et al, 1978). At present, local production has been fully corroborated in brain tissue and cultured neurons (de Pablo and de la Rosa, 1995;Nemoto et al, 2014). Specific functions of insulin in brain include regulation of food intake, body weight, reproduction, and glycemic control in the hypothalamus, in addition to the promotion of learning and memory in the hippocampus (Ghasemi et al, 2013;Wada et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

et al. 2017

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Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.

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“…The CNS is a well-recognized site of action of insulin and insulin-like factors (IGF-I and -II) 55 . The insulin gene is transcriptionally active in tissues other than the pancreas, although at a much lower level, and local insulin gene expression has been demonstrated in the brain and retina [56][57][58] . Furthermore, potential autocrine/paracrine effects of insulin/proinsulin in the CNS have been suspected for some time, based on the local presence of moderate insulin/proinsulin levels that are independent of peripheral levels 56,59 .…”

Section: Proinsulin a Candidate Drug For Neurodegenerative Conditionmentioning

confidence: 99%

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

Rosa¹,

Hernández‐Sánchez²

2018

Drug Discovery

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As an extension of the central nervous system (CNS), the retina shares with the brain certain developmental, physiological, and pathological characteristics. However, the underlying mechanisms and pathological signs common to neurodegenerative conditions of both the retina and brain have been relatively overlooked. In animal models and in human patients, marked retinal alterations have been demonstrated in Alzheimer´s disease, Parkinson´s disease, and multiple sclerosis, among other pathologies. Furthermore, neurodegeneration of the retina and brain appears to be mediated by similar mechanisms, which include protein aggregation, neuroinflammation, and cell death. Analysis of the retina, which is easily accessible to objective techniques, may therefore constitute an effective tool for the screening and follow-up of CNS neurodegeneration. Moreover, patients with retinal neurodegeneration could potentially benefit from the broad array of pharmacological compounds that have been designed and tested for the treatment of the aforementioned CNS pathologies. Supporting this view, we have shown that GSK-3 inhibitors, which have already been tested in clinical trials to treat several neurodegenerative conditions of the brain, attenuate retinal damage and vision loss in a mouse model of retinitis pigmentosa. Furthermore, systemic proinsulin treatment preserves visual and cognitive function in mouse models of retinitis pigmentosa and precocious aging, respectively.

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New insights concerning insulin synthesis and its secretion in rat hippocampus and cerebral cortex: Amyloid-β1–42-induced reduction of proinsulin level via glycogen synthase kinase-3β

Cited by 29 publications

References 34 publications

The nature, significance, and glucagon‐like peptide‐1 analog treatment of brain insulin resistance in Alzheimer's disease

The nature, significance, and glucagon‐like peptide‐1 analog treatment of brain insulin resistance in Alzheimer's disease

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

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