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.

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 Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer’s Disease

2019 ◽  
Vol 20 (12) ◽  
pp. 3030 ◽  
Author(s):  
Soo Jung Shin ◽  
Seong Gak Jeon ◽  
Jin-il Kim ◽  
Yu-on Jeong ◽  
Sujin Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Formation ◽  
Experimental Models ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Red Ginseng ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 52 (1) ◽  
pp. 223-242 ◽  
Author(s):  
Patricia R. Spilman ◽  
Veronique Corset ◽  
Olivia Gorostiza ◽  
Karen S. Poksay ◽  
Veronica Galvan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Nepeta menthoides Boiss. & Buhse, an endemic species in Iran: A review of traditional uses, phytochemistry and pharmacology

2019 ◽  
Vol 8 (3) ◽  
pp. 194-204
Author(s):  
Zahra Memariani ◽  
Atena Rahimi ◽  
Mohammad Hosein Farzaei ◽  
Niloofar Zakaria Nejad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endemic Species ◽  
Scientific Evidence ◽  
Therapeutic Effects ◽  
Lavandula Stoechas ◽  
Traditional Persian Medicine ◽  
Memory Enhancing

Nepeta menthoides Boiss & Buhse is one of the endemic species in Iran. Named Ostokhodus, it is almost used as substitute of the Lavandula stoechas –the original Ostokhodus- in traditional Persian medicine (TPM) over the time and widely used for the management of some ailments such as anxiety, depression, dementia and chronic pain. The aim of this study is to review the pharmacological and phytochemical evidence on Nepeta menthoides for the assessment of the recommended traditional indications of this herb. In this review, all the relevant articles that met our inclusion criteria [English or Persian articles, having full text, evaluating therapeutic effects of N. menthoides and dated mainly from the year 1980 to 2018] were included by searching studies in PubMed, Scopus, Google Scholar, Web of Science, and SID. The search terms were "Nepeta menthoides, "Ostokhodus". Triterpenes and monoterpenes were the most chemicals reported from essential oil of N. menthoides. Several pharmacological properties via in vitro, in vivo and clinical studies have been reported including antioxidant, anti-inflammatory, anti-nociceptive, antidepressant and anxiolytic, anticholinesterase, neuroprotective, memory enhancing, anti-Alzheimer’s disease, anticancer and effect on opioid dependence. Some proposed traditional indications of this herb in TPM books are in accordance with pharmacological evidence like anti-nociceptive, anti-seizure, anti-Alzheimer’s disease, memory enhancing, neuroprotective, antidepressant, anxiolytic activity and anti-infective properties. Although some properties in TPM, such as anti-tussive and gastrotonic effects are not supported by scientific evidence, they need more investigations.

scholarly journals A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing

2021 ◽  
Author(s):  
Sarah Garder ◽  
Catharine Brady ◽  
Cameron Keeton ◽  
Anuj K Yadav ◽  
Sharath C Mallojjala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photoacoustic Imaging ◽  
Disease Model ◽  
Photoacoustic Signal ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

<p>In the context of deep-tissue disease biomarker detection and analyte sensing of biologically relevant species, the impact of photoacoustic imaging has been profound. However, most photoacoustic imaging agents to date are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for photoacoustic applications (e.g., high fluorescence quantum yield). Herein, we introduce two effective modifications to the hemicyanine dye to afford PA-HD, a new dye scaffold optimized for photoacoustic probe development. We observed a significant increase in the photoacoustic output, representing an increase in sensitivity of 4.8-fold and a red-shift of the λ<sub>abs</sub> from 690 nm to 745 nm to enable ratiometric imaging. Moreover, to demonstrate the generalizability and utility of our remodeling efforts, we developed three probes using common analyte-responsive triggers for beta-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and hydrogen peroxide (PA-HD-H<sub>2</sub>O<sub>2</sub>). The performance of each probe (responsiveness, selectivity) was evaluated <i>in vitro</i> and <i>in cellulo</i>. To showcase the enhance properties afforded by PA-HD for <i>in vivo</i> photoacoustic imaging, we employed an Alzheimer’s disease model to detect H<sub>2</sub>O<sub>2</sub>. In particular, the photoacoustic signal at 735 nm in the brains of 5xFAD mice (a murine model of Alzheimer’s disease) increased by 1.72 ± 0.20-fold relative to background indicating the presence of oxidative stress, whereas the change in wildtype mice was negligible (1.02 ± 0.14). These results were confirmed via ratiometric calibration which was not possible using the parent HD platform.</p>

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 CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTL in vivo over-expression has a mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

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