Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling

Kang, Somang; Kim, Chul Hoon; Jung, Hosung; Kim, Eosu; Song, Ho Taek; Lee, Jong Eun

doi:10.1016/j.neuropharm.2016.10.029

Cited by 76 publications

(58 citation statements)

References 75 publications

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“…Various vitamins, such as Vitamin A, B, C, and K, are proven to be effective in AD treatment 99. We have also demonstrated the effect of agmatine, a polyamine that works as an antioxidant, on mice displaying AD like alterations induced by long term high-fat diet and rats with streptozotocin-induced AD 51100. Oxidative stress is one of the most important factors involved in the development and progression of AD.…”

Section: Possible Cause Of Alzheimer's Disease: Reduced Antioxidant Dmentioning

confidence: 82%

Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

2017

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Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD is characterized by the extracellular amyloid beta (Aβ) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs). Recently, as aging has become a familiar phenomenon around the world, patients with AD are increasing in number. Thus, many researchers are working toward finding effective therapeutics for AD focused on Aβ hypothesis, although there has been no success yet. In this review paper, we suggest that AD is a metabolic disease and that we should focus on metabolites that are affected by metabolic alterations to find effective therapeutics for AD. Aging is associated with not only AD but also obesity and type 2 diabetes (T2DM). AD, obesity, and T2DM share demographic profiles, risk factors, and clinical and biochemical features in common. Considering AD as a kind of metabolic disease, we suggest insulin, adiponectin, and antioxidants as mechanistic links among these diseases and targets for AD therapeutics. Patients with AD show reduced insulin signal transductions in the brain, and intranasal injection of insulin has been found to have an effect on AD treatment. In addition, adiponectin is decreased in the patients with obesity and T2DM. This reduction induces metabolic dysfunction both in the body and the brain, leading to AD pathogenesis. Oxidative stress is known to be induced by Aβ and NFTs, and we suggest that oxidative stress caused by metabolic alterations in the body induce brain metabolic alterations, resulting in AD.

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Section: Possible Cause Of Alzheimer's Disease: Reduced Antioxidant Dmentioning

confidence: 82%

Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

2017

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“…Furthermore, some clinical studies have found that patients with diabetes have altered cerebrospinal fluid Aβ and tau abundance and lower levels of cognition, whereas data from preclinical and small clinical trials suggest, in several but not all studies, that treatment with insulin and agents that promote insulin signaling may reduce neuropathology and improve cognition in diabetes and AD. [6][7][8] Pathophysiologic processes downstream from insulin signaling, such as alterations in serine /threonine-protein kinase (AKT), are also thought to be involved in AD pathology, including Aβ deposition and tau phosphorylation. 9 This study examined the associations of key insulin signaling molecules (insulin receptor substrate-1 [IRS1] and AKT) with AD neuropathology and cognitive function in persons with or without diabetes.…”

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confidence: 99%

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Arvanitakis

Wang

Capuano

et al. 2020

Annals of Neurology

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Objective To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. Methods This clinical–pathologic study was derived from a community‐based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme‐linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. Results Brain insulin receptor substrate‐1 (IRS1) phosphorylation (pS307IRS1/total IRS1) and serine/threonine‐protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). Interpretation Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. ANN NEUROL 2020;88:513–525

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“…Moreover, the beneficial effects of agmatine have been observed on ischemic-hypoxic lesions, on glutamate-induced neurotoxicity by activating the imidazoline receptors [28,29]. It was also demonstrated that agmatine administration improves learning activity and memory of rats in experimental models of Alzheimer's disease and streptozotocin-induced type two diabetes mellitus [22,30].…”

Section: The Involvement Of the Imidazoline System In The Mediation Omentioning

confidence: 96%

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

Mititelu-Tarțău¹,

Bogdan²,

Gheorman³

et al. 2019

Neuroprotection

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Due to brain plasticity, the nervous system is capable of manifesting behavioral variations, adapted to the influences from both external and internal environment. Multiple neurotransmitters are involved in the mediation of pathological processes at the molecular, cellular, regional, and interregional levels participating in cerebral plasticity, their intervention being responsible for various structural, functional, and behavioral disturbances. The current therapeutic strategies in neuroprotection aim at blocking on different levels, the molecular cascades of the pathophysiological mechanisms responsible for neuronal dysfunctions and ultimately for neuronal death. Different agents influencing these neurotransmitters have demonstrated beneficial effects in neurogenesis and neuroprotection, proved in experimental animal models of focal and global ischemic injuries. Serotonin, dopamine, glutamate, N-methyl-D-aspartate, and nitric oxide have been shown to play a significant role in modulating nervous system injuries. The imidazoline system is one of the important systems involved in human brain functioning. Experimental investigations have revealed the cytoprotective effects of imidazoline I2 receptor ligands against neuronal injury induced by hypoxia in experimental animals. The neuroprotective effects were also highlighted for kappa and delta receptors, whose agonists demonstrated the ability to reduce architectural lesions and to recover neuronal functions of animals with experimentally induced brain ischemia.

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Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling

Cited by 76 publications

References 75 publications

Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease

Brain Insulin Signaling, Alzheimer Disease Pathology, and Cognitive Function

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

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