Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

scholarly journals Mechanistic Aspects of Apiaceae Family Spices in Ameliorating Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1571
Author(s):  
Niti Sharma ◽  
Mario A. Tan ◽  
Seong Soo A. An
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Scientific Literature ◽  
Comprehensive Evaluation ◽  
Amyloid Plaque ◽  
Plaque Formation ◽  
New Strategies

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. In an effort to search for new strategies for treating AD, natural products have become candidates of choice. Plants are a rich source of bioactive and effective compounds used in treating numerous diseases. Various plant extracts are known to display neuroprotective activities by targeting different pathophysiological pathways in association with the diseases, such as inhibiting enzymes responsible for degrading neurotransmitters, reducing oxidative stress, neuroprotection, inhibiting amyloid plaque formation, and replenishing mitochondrial function. This review presented a comprehensive evaluation of the available scientific literature (in vivo, in vitro, and in silico) on the neuroprotective mechanisms displayed by the extracts/bioactive compounds from spices belonging to the Apiaceae family in ameliorating AD.

scholarly journals Resveratrol and Neuroprotection: Impact and Its Therapeutic Potential in Alzheimer's Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Md. Habibur Rahman ◽  
Rokeya Akter ◽  
Tanima Bhattacharya ◽  
Mohamed M. Abdel-Daim ◽  
Saad Alkahtani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Tau Proteins ◽  
Amyloid Peptides ◽  
Work Done

Alzheimer’s disease (AD) is a progressive cortex and hippocampal neurodegenerative disease which ultimately causes cognitively impaired decline in patients. The AD pathogen is a very complex process, including aggregation of Aβ (β-amyloid peptides), phosphorylation of tau-proteins, and chronic inflammation. Exactly, resveratrol, a polyphenol present in red wine, and many plants are indicated to show the neuroprotective effect on mechanisms mostly above. Resveratrol plays an important role in promotion of non-amyloidogenic cleavage of the amyloid precursor protein. It also enhances the clearance of amyloid beta-peptides and reduces the damage of neurons. Most experimental research on AD and resveratrol has been performed in many species, both in vitro and in vivo, during the last few years. Nevertheless, resveratrol’s effects are restricted by its bioavailability in the reservoir. Therefore, scientists have tried to improve its efficiency by using different methods. This review focuses on recent work done on the cell and animal cultures and also focuses on the neuroprotective molecular mechanisms of resveratrol. It also discusses about the therapeutic potential onto the treatment of AD.

scholarly journals Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Zhongrui Yan ◽  
Xianjing Shi ◽  
Hui Wang ◽  
Cuiping Si ◽  
Qian Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Model Of Alzheimer’S Disease ◽  
Neurotrophin 3

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.

scholarly journals Glutamine Improves Oxidative Stress through the Wnt3a/β-Catenin Signaling Pathway in Alzheimer’s Disease In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Yuan Wang ◽  
Qiang Wang ◽  
Jie Li ◽  
Gang Lu ◽  
Zhibin Liu
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Pc12 Cells ◽  
Stress Injury ◽  
Mda Content ◽  
Samp8 Mice

Background/Aims. Alzheimer’s disease (AD) is the most common neurodegenerative disease, and all researchers working in this field agree that oxidative stress is intimately associated with Alzheimer disease. In this study, we hypothesized that glutamine (Gln) offers protection against oxidative stress injury in SAMP8 mice as well as the underlying mechanism. Methods. The SAMP8 mice received glutamine intragastrically for 8 consecutive weeks to evaluate the protective effect of glutamine on oxidative stress in AD mice involving Wnt3a/β-catenin signaling pathway. In addition, rat pheochromocytoma tumor cell line PC12 was pretreated with 32 μM glutamine for 2 h followed by 24 h incubation with 40 μM Aβ25-35 to obtain in vitro data. Results. In vivo the administration of glutamine was found to ameliorate behavioral deficits and neuron damage, increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-XP) activity, reduce the malondialdehyde (MDA) content, and activate the Wnt3a/β-catenin signaling pathway in SAMP8 mice. In vitro glutamine treatment decreased the toxicity of Aβ25-35 on PC12 cells and prevented apoptosis. Additionally, glutamine treatment increased SOD and GSH-XP activity and decreased MDA content and increased Wnt3a and β-catenin protein levels. Interestingly, the DKK-1 (Wnt3a/β-catenin pathway inhibitor) decreased the antioxidant capacity of glutamine in Aβ25-35-treated PC12 cells. Conclusion. This study suggests that glutamine could protect against oxidative stress-induced injury in AD mice via the Wnt3a/β-catenin signaling pathway.

scholarly journals The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

2019 ◽  
Vol 20 (18) ◽  
pp. 4641 ◽  
Author(s):  
Alfonso Gautieri ◽  
Marten Beeg ◽  
Marco Gobbi ◽  
Federica Rigoldi ◽  
Laura Colombo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Neurological Diseases ◽  
Fibrillar Structure ◽  
Structure Based Drug Design

The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer’s disease.

scholarly journals Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?

2021 ◽  
Vol 22 (16) ◽  
pp. 8769
Author(s):  
Anaïs Vignon ◽  
Lucie Salvador-Prince ◽  
Sylvain Lehmann ◽  
Véronique Perrier ◽  
Joan Torrent
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Experimental Models ◽  
Tau Proteins ◽  
Human Pathology ◽  
Set Up

Discovered more than a century ago, Alzheimer’s disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.

scholarly journals Resveratrol as a Therapeutic Agent for Alzheimer’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Teng Ma ◽  
Meng-Shan Tan ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Agent ◽  
Red Wine ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Neuroprotective Effects

Alzheimer’s disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Aβaccumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD.

scholarly journals Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

2020 ◽  
Author(s):  
Evgenia Salta ◽  
Hannah Walgrave ◽  
Sriram Balusu ◽  
Elke Vanden Eynden ◽  
Sarah Snoeck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Memory Decline ◽  
Human Neural Stem Cells ◽  
Neurogenic Niche

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

Oxymatrine attenuates amyloid beta 42 (Aβ1–42)-induced neurotoxicity in primary neuronal cells and memory impairment in rats

2019 ◽  
Vol 97 (2) ◽  
pp. 99-106 ◽  
Author(s):  
Peiliang Dong ◽  
Xiaomeng Ji ◽  
Wei Han ◽  
Hua Han
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Neuronal Cells ◽  
Morris Water Maze Test ◽  
Dependent Manner ◽  
Amyloid Beta 42

Amyloid beta 42 (Aβ1–42)-induced oxidative stress causes the death of neuronal cells and is involved in the development of Alzheimer’s disease. Oxymatrine (OMT) inhibits oxidative stress. In this study, we investigated the effect of OMT on Aβ1–42-induced neurotoxicity in vivo and in vitro. In the Morris water maze test, OMT significantly decreased escape latency and increased the number of platform crossings. In vitro, OMT markedly increased cell viability and superoxide dismutase activity. Moreover, OMT decreased lactate dehydrogenase leakage, malondialdehyde content, and reactive oxygen species in a dose-dependent manner. OMT upregulated the ratio of Bcl-2/Bax and downregulated the level of caspase-3. Furthermore, OMT inhibited the activation of MAP kinase (ERK 1/2, JNK) and nuclear factor κB. In summary, OMT may potentially be used in the treatment of Alzheimer’s disease.

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