scholarly journals Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1992 ◽  
Author(s):  
Firas H. Bazzari ◽  
Dalaal M. Abdallah ◽  
Hanan S. El-Abhar
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Chenodeoxycholic Acid ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Significant Difference

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease

2021 ◽  
pp. 1-9
Author(s):  
Fan Ye ◽  
Anshi Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Biogenesis ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Neuronal Morphology ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Class Iii ◽  
Peroxisome Proliferator Activated Receptor

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease

2021 ◽  
pp. 1-17
Author(s):  
Jessica Lynn ◽  
Mingi Park ◽  
Christiana Ogunwale ◽  
George K. Acquaah-Mensah
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Insulin Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Main Component ◽  
The Impact

Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

scholarly journals Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Manoj Govindarajulu ◽  
Priyanka D. Pinky ◽  
Jenna Bloemer ◽  
Nila Ghanei ◽  
Vishnu Suppiramaniam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Effects ◽  
Therapeutic Potential ◽  
Protein Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Continuous Increase ◽  
Therapeutic Benefits ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

scholarly journals Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hong-Jie Chen ◽  
Chih-Yuan Ko ◽  
Jian-Hua Xu ◽  
Yu-Chu Huang ◽  
James Swi-Bea Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Ethyl Acetate ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Lipid Accumulation ◽  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Glucose Transporter 2 ◽  
Tnf Α ◽  
Mouse Hepatocytes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

Roles of Cannabidiol in the treatment and prevention of Alzheimer’s disease by multi-target actions

2021 ◽  
Vol 21 ◽  
Author(s):  
Xiao- Bei Zhang ◽  
Jintao Li ◽  
Juanhua Gu ◽  
Yue-Qin Zeng
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transient Receptor Potential ◽  
Senile Plaques ◽  
Memory Loss ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor

: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol(CBD) possesses various pharmacological activities including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system（eCBs）, the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome proliferator-activated receptor (PPAR) receptor.

scholarly journals PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

2016 ◽  
Vol 113 (43) ◽  
pp. 12292-12297 ◽  
Author(s):  
Loukia Katsouri ◽  
Yau M. Lim ◽  
Katrin Blondrath ◽  
Ioanna Eleftheriadou ◽  
Laura Lombardero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Lentiviral Vector ◽  
Disease Model ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects ◽  
Peroxisome Proliferator Activated Receptor

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains

1999 ◽  
Vol 254 (3) ◽  
pp. 582-586 ◽  
Author(s):  
Yoshihisa Kitamura ◽  
Shun Shimohama ◽  
Hideyasu Koike ◽  
Jun-ichi Kakimura ◽  
Yasuji Matsuoka ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals The PPAR-γAgonist 15-Deoxy-Δ12,14-ProstaglandinJ2Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer's Disease

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Jihong Xu ◽  
Steven W. Barger ◽  
Paul D. Drew
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Th17 Cells ◽  
Human Subjects ◽  
T Cell Response ◽  
Great Promise ◽  
Peroxisome Proliferator ◽  
Cns Inflammation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Synergistic Induction

Accumulation of amyloid-βpeptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβdeposits has been placed in strategies involving immunization against the Aβpeptide. Initial Aβimmunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically,CD4+Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβimmunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γagonist 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γagonists may be effective in modulating the development of AD.

scholarly journals Insulin and Insulin Resistance in Alzheimer’s Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9987
Author(s):  
Aleksandra Sędzikowska ◽  
Leszek Szablewski
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Cell Growth ◽  
Glucose Metabolism ◽  
Insulin Signaling ◽  
Brain Aging ◽  
Mapk Pathway ◽  
Metabolic Effects ◽  
Peripheral Tissues

Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood–brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer’s disease.

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