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.

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 Formation of Toxic Amyloid Fibrils by Amyloidβ-Protein on Ganglioside Clusters

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Katsumi Matsuzaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Physicochemical Properties ◽  
Lipid Rafts ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Protein A ◽  
Pivotal Role ◽  
Membrane Interaction

It is widely accepted that the conversion of the soluble, nontoxic amyloidβ-protein (Aβ) monomer to aggregated toxic Aβrich inβ-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβin vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβaggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβamyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.

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 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.

Aromatase/Seladin-1 Interactions in Human Neuronal Cell Culture, the Hippocampus of Healthy Rats and Transgenic Alzheimer’s Disease Mice

Pharmacology ◽  
2018 ◽  
Vol 102 (1-2) ◽  
pp. 42-52 ◽  
Author(s):  
Hande Karahan ◽  
Sevda Lüle ◽  
Pelin Kelicen-Uğur
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Human Neuroblastoma ◽  
Protein Levels ◽  
Genes Encoding ◽  
Estrogen Biosynthesis

Background/Aims: Decreasing levels of aromatase and seladin-1 could be one of the molecular mechanisms of Alzheimer’s disease (AD). Aromatase is an enzyme that catalyzes estrogen biosynthesis from androgen precursors, and seladin-1 is an enzyme that converts desmosterol to cholesterol, which is the precursor of all hormones. Verifying the potential relationship between these proteins and accordingly determining new therapeutic targets constitute the aims of this study. Methods: Changes in protein levels were compared in vitro in aromatase and seladin-1 inhibitor-administered human neuroblastoma (SH-SY5Y) cells in vivo in intracerebroventricular (icv) aromatase or seladin-1 inhibitor-administered rats, as well as in transgenic AD mice in which the genes encoding these proteins were knocked out. Results and Conclusions: In the cell cultures, we observed that seladin-1 protein levels increased after aromatase enzyme inhibition. The hippocampal aromatase protein levels decreased following chronic seladin-1 inhibition in icv inhibitor-administered rats; however, the aromatase levels in the dentate gyrus of seladin-1 knockout (SelKO) AD male mice increased. These findings indicate a partial relationship between these proteins and their roles in AD pathology.

scholarly journals Effects of Tea Catechins on Alzheimer’s Disease: Recent Updates and Perspectives

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2357 ◽  
Author(s):  
Kazuki Ide ◽  
Norihiro Matsuoka ◽  
Hiroshi Yamada ◽  
Daisuke Furushima ◽  
Koji Kawakami
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
In Vivo Studies ◽  
Bioactive Components ◽  
Current Review ◽  
Ad Prevention

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders worldwide. Its incidence is gradually increasing because of an aging demographic. Therefore, AD prevention and modification is important to improve the health status of older adults. Oxidative stress is a component of the pathological mechanisms underlying AD. It is caused by a disruption of the balance between reactive oxygen species and antioxidant molecules. This imbalance also causes neuroinflammation. Catechins, which are bioactive components of tea, have antioxidative and anti-inflammatory effects. Moreover, other potential properties related to AD prevention and modification have been reported in in vitro and in vivo studies. Several clinical studies have also been conducted to date. The current review summarizes recent updates and perspectives of the effects of catechins on AD based on the molecular mechanisms and related clinical studies.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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