scholarly journals Enhancement of Insulin/PI3K/Akt Signaling Pathway and Modulation of Gut Microbiome by Probiotics Fermentation Technology, a Kefir Grain Product, in Sporadic Alzheimer’s Disease Model in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Nesrine S. El Sayed ◽  
Esraa A. Kandil ◽  
Mamdooh H. Ghoneum
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Gut Microbiome ◽  
Akt Signaling ◽  
Sporadic Alzheimer’S Disease ◽  
Gsk 3Β ◽  
Fermentation Technology

Sporadic Alzheimer’s disease (AD) is the most common neurodegenerative disorder with cognitive dysfunction. Remarkably, alteration in the gut microbiome and resultant insulin resistance has been shown to be connected to metabolic syndrome, the crucial risk factor for AD, and also to be implicated in AD pathogenesis. Thus, this study, we assessed the efficiency of probiotics fermentation technology (PFT), a kefir product, in enhancing insulin signaling via modulation of gut microbiota to halt the development of AD. We also compared its effectiveness to that of pioglitazone, an insulin sensitizer that has been confirmed to substantially treat AD. AD was induced in mice by a single injection of intracerebroventricular streptozotocin (STZ; 3 mg/kg). PFT (100, 200, 400 mg/kg) and pioglitazone (30 mg/kg) were administered orally for 3 weeks. Behavioral tests were conducted to assess cognitive function, and hippocampal levels of acetylcholine (Ach) and β-amyloid (Aβ1–42) protein were assessed along with histological examination. Moreover, the expression of the insulin receptor, insulin degrading enzyme (IDE), and the phosphorylated forms of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), mammalian target of rapamycin (mTOR), and tau were detected. Furthermore, oxidative stress and inflammatory biomarkers were estimated. Treatment with PFT reversed STZ-induced neurodegeneration and cognitive impairment, enhanced hippocampal Ach levels, and reduced Aβ1–42 levels after restoration of IDE activity. PFT also improved insulin signaling, as evidenced by upregulation of insulin receptor expression and activation of PI3K/Akt signaling with subsequent suppression of GSK-3β and mTOR signaling, which result in the downregulation of hyperphosphorylated tau. Moreover, PFT significantly diminished oxidative stress and inflammation induced by STZ. These potential effects were parallel to those produced by pioglitazone. Therefore, PFT targets multiple mechanisms incorporated in the pathogenesis of AD and hence might be a beneficial therapy for AD.

scholarly journals Antia, a Natural Antioxidant Product, Attenuates Cognitive Dysfunction in Streptozotocin-Induced Mouse Model of Sporadic Alzheimer’s Disease by Targeting the Amyloidogenic, Inflammatory, Autophagy, and Oxidative Stress Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Nesrine S. El Sayed ◽  
Mamdooh H. Ghoneum
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Protective Effect ◽  
Cognitive Dysfunction ◽  
Protective Role ◽  
Sporadic Alzheimer’S Disease ◽  
Stat3 Pathway ◽  
And Oxidative Stress

Background. Many neurodegenerative diseases such as Alzheimer’s disease are associated with oxidative stress. Therefore, antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases. Objective. We investigated the ability of the antioxidant Antia to exert a protective effect against sporadic Alzheimer’s disease (SAD) induced in mice. Antia is a natural product that is extracted from the edible yamabushitake mushroom, the gotsukora and kothala himbutu plants, diosgenin (an extract from wild yam tubers), and amla (Indian gooseberry) after treatment with MRN-100. Methods. Single intracerebroventricular (ICV) injection of streptozotocin (STZ) (3 mg/kg) was used for induction of SAD in mice. Antia was injected intraperitoneally (i.p.) in 3 doses (25, 50, and 100 mg/kg/day) for 21 days. Neurobehavioral tests were conducted within 24 h after the last day of injection. Afterwards, mice were sacrificed and their hippocampi were rapidly excised, weighed, and homogenized to be used for measuring biochemical parameters. Results. Treatment with Antia significantly improved mice performance in the Morris water maze. In addition, biochemical analysis showed that Antia exerted a protective effect for several compounds, including GSH, MDA, NF-κB, IL-6, TNF-α, and amyloid β. Further studies with western blot showed the protective effect of Antia for the JAK2/STAT3 pathway. Conclusions. Antia exerts a significant protection against cognitive dysfunction induced by ICV-STZ injection. This effect is achieved through targeting of the amyloidogenic, inflammatory, and oxidative stress pathways. The JAK2/STAT3 pathway plays a protective role for neuroinflammatory and neurodegenerative diseases such as SAD.

A multifunctional compound ebselen reverses memory impairment, apoptosis and oxidative stress in a mouse model of sporadic Alzheimer's disease

2019 ◽  
Vol 109 ◽  
pp. 107-117 ◽  
Author(s):  
Franciele Martini ◽  
Suzan Gonçalves Rosa ◽  
Isabella Pregardier Klann ◽  
Bruna Cruz Weber Fulco ◽  
Fabiano Barbosa Carvalho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Impairment ◽  
Sporadic Alzheimer’S Disease ◽  
And Oxidative Stress

scholarly journals Insulin Receptor Expression and Activity in the Brains of Nondiabetic Sporadic Alzheimer’s Disease Cases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Lap Ho ◽  
Shrishailam Yemul ◽  
Lindsay Knable ◽  
Pavel Katsel ◽  
Rudy Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Hippocampal Formation ◽  
Receptor Expression ◽  
Sporadic Alzheimer’S Disease ◽  
Study Support ◽  
Insulin Receptor Expression ◽  
Signaling Components

We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβas surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer’s disease (AD) cases. We found no significant changes in the brain contents of total IRβor [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβand [Tyr1162/1163]-phosphorylated IRβlevels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/βin brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.

scholarly journals Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer’s disease

2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Dario Confettura ◽  
Eleonora Cuboni ◽  
Mohamed Rafeet Ammar ◽  
Shaobo Jia ◽  
Guilherme M. Gomes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
The Metabolic Syndrome ◽  
Amyloid Load ◽  
Underlying Mechanisms

Abstract Background The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. Methods We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. Results We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. Conclusions Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.

Ebselen reversed peripheral oxidative stress induced by a mouse model of sporadic Alzheimer's disease

2020 ◽  
Vol 47 (3) ◽  
pp. 2205-2215
Author(s):  
Isabella Pregardier Klann ◽  
Franciele Martini ◽  
Suzan Gonçalves Rosa ◽  
Cristina Wayne Nogueira
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Sporadic Alzheimer’S Disease

scholarly journals Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1257
Author(s):  
Maria Assunta Potenza ◽  
Luca Sgarra ◽  
Vanessa Desantis ◽  
Carmela Nacci ◽  
Monica Montagnani
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Mitochondrial Activity ◽  
Enhanced Production ◽  
The Common ◽  
The Brain

A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.

scholarly journals Protective Effect of Biobran/MGN-3 against Sporadic Alzheimer’s Disease Mouse Model: Possible Role of Oxidative Stress and Apoptotic Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Mamdooh H. Ghoneum ◽  
Nesrine S. El Sayed
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protective Effect ◽  
Amyloid Beta ◽  
Neuronal Damage ◽  
Histopathological Examination ◽  
Intercellular Adhesion Molecule ◽  
Related Factor ◽  
Sporadic Alzheimer’S Disease

Alzheimer’s disease (AD) is a debilitating and irreversible brain disease that affects an increasing number of aged individuals, mandating the development of protective nutraceuticals. Biobran/MGN-3, an arabinoxylan from rice bran, has potent antioxidant, antiaging, and immunomodulatory effects. The aim of the present study was to investigate the protective effect of Biobran against sporadic Alzheimer’s disease (SAD). SAD was induced in mice via intracerebroventricular injection of streptozotocin (STZ) (3 mg/kg). STZ-treated mice were administered with Biobran for 21 days. The effects of Biobran on memory and learning were measured via the Morris water maze, novel object recognition, and Y-maze tests. Biomarkers for apoptosis, oxidative stress, and amyloidogenesis were measured using ELISA and western blot analysis. Histopathological examination was performed to confirm neuronal damage and amyloid-beta deposition. Biobran reversed the spatial memory deficit in SAD-induced mice, and it increased the expression of glutathione, reduced malondialdehyde, decreased IL-6, decreased intercellular adhesion molecule-1 (ICAM-1), and significantly increased nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). Moreover, Biobran exerted a protective effect against amyloid-beta-induced apoptosis via the suppression of both cleaved caspase-3 and the proapoptotic protein Bax and via the upregulation of the antiapoptotic protein Bcl-2. Furthermore, it reduced the expression of forkhead box class O proteins. It could be concluded from this study that Biobran may be a useful nutritional antioxidant agent for protection against SAD through its activation of the gene expression of Nrf2/ARE, which in turn modulates the apoptotic and amyloidogenic pathways.

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