scholarly journals Intra- and extracellular β-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stefania Forner ◽  
Alessandra C. Martini ◽  
G. Aleph Prieto ◽  
Cindy T. Dang ◽  
Carlos J. Rodriguez-Ortiz ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Data Interpretation ◽  
Long Term Potentiation ◽  
Brain Parenchyma ◽  
Aβ Oligomers ◽  
Age Related ◽  
Synaptic Failure ◽  
Β Amyloid

Abstract Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as β-amyloid (Aβ) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aβ either intra or extracellularly. We observed that expression of Aβ in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aβ inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aβ in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aβ oligomers both in vivo and in vitro.

scholarly journals A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Shankar J. Chinta ◽  
Subramanian Rajagopalan ◽  
Abirami Ganesan ◽  
Julie K. Andersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Oxidative And Nitrosative Stress ◽  
Prolyl Hydroxylases ◽  
Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

scholarly journals Aqueous Extract of Dendropanax morbiferus Leaves Effectively Alleviated Neuroinflammation and Behavioral Impediments in MPTP-Induced Parkinson’s Mouse Model

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Shin-Young Park ◽  
Govindarajan Karthivashan ◽  
Hyun Myung Ko ◽  
Duk-Yeon Cho ◽  
Joonsoo Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Major Constituent ◽  
Bioactive Constituents ◽  
Endemic Plant ◽  
Leaf Extracts ◽  
Age Related ◽  
Dendropanax Morbifera

Parkinson’s disease (PD) is a commonly reported age-related neurodegenerative disorder. Microglial-mediated neuroinflammation is one of the cardinal hallmarks of various neurodegenerative disorders, including PD progression. Inadequate therapeutic strategies and substantial adverse effects of well-established drug candidates demand new therapeutic leads to treat PD. Dendropanax morbifera (DM) is an endemic plant species of South Korea, and it has been used extensively as traditional medicine to treat numerous clinical complications. In this study, we conducted an initial profiling of the few major phytoconstituents of aqueous DM leaf extracts (DML) and quantified the same using high-performance liquid chromatography tandem mass spectrometry with electrospray ionization (HPLC-ESI-MS/MS). We subsequently evaluated the antineuroinflammatory activity and ameliorative potential of DML in both in vitro and in vivo experimental PD models. The prophylactic treatment of DML effectually improved the behavioral deficits, curbed the microglial-mediated neuroinflammation, and protected dopaminergic (DA) neuronal loss by restoring tyrosine hydroxylase (TH) levels in brain tissue of the MPTP-induced PD mouse model. We conducted chromatographic profiling and identified chlorogenic acid (CA) as a major constituent (19.5 mg/g of BuOH fraction), which has been well documented as an antioxidant and anti-inflammatory agent. This was found to be in harmony with our in vitro results, where DML suppressed the level of inflammatory mediators and allied the signaling pathway in LPS-stimulated microglial cells. The results of our study indicate that DML and its bioactive constituents can be developed as potential therapeutic candidates against progressive PD complications.

Investigation of anti-Alzheimer’s activity of aqueous extract of areca nuts (Areca catechu L.): In vitro and in vivo studies

2021 ◽  
Vol 20 (4) ◽  
pp. 406-415
Author(s):  
Mahboubeh Bozorgi ◽  
◽  
Zahra Najafi ◽  
Sahar Omidpanah ◽  
Arash Sadri ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
In Vivo Studies ◽  
Memory Impairments ◽  
Age Related ◽  
Areca Catechu ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer’s activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid β (Aβ) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

scholarly journals Methionine-35 of Aβ(1–42): Importance for Oxidative Stress in Alzheimer Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
D. Allan Butterfield ◽  
Rukhsana Sultana
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Underlying Disease ◽  
Methionine Residue ◽  
Neurotoxic Peptide ◽  
Age Related

Alzheimer disease (AD) is an age-related progressive neurodegenerative disorder. This devastating disease is characterized by the presence of senile plaques (SP), neurofibrillary tangles (NFTs), and loss of synapses. Amyloid beta-peptide 1–42 (Aβ(1–42)) is the main component of SP and is pivotal to AD pathogenesis. Brain of subjects with AD and arguably its earliest manifestation, mild cognitive impairment (MCI), demonstrate increased levels of oxidative stress markers. Our laboratory combined these two aspects of AD and MCI and proposed the Aβ(1–42)-associated free radical oxidative stress hypothesis to explain oxidative stress under which the MCI and AD brain exist and the loss of synapses in both disorders. A large number of in vitro and in vivo studies showed that Aβ causes protein oxidation, lipid peroxidation, reactive oxygen species formation, and cell death in neuronal and synaptosomal systems. Methionine located at residue 35 of Aβ(1–42) is an important contributor to the oxidative stress associated with this neurotoxic peptide. In this paper, we summarize studies involving Met-35 of Aβ(1–42). Understanding the role of the single methionine residue of Aβ(1–42) may help in understanding underlying disease mechanisms in AD and MCI.

Antibodies against β-amyloid reduce aβ oligomers, glycogen synthase kinase-3β activation and τ phosphorylation in vivo and in vitro

2006 ◽  
Vol 83 (3) ◽  
pp. 374-384 ◽  
Author(s):  
Qiu-Lan Ma ◽  
Giselle P. Lim ◽  
Marni E. Harris-White ◽  
Fusheng Yang ◽  
Surendra S. Ambegaokar ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Aβ Oligomers ◽  
Β Amyloid

A spiropyran-based fluorescent probe for the specific detection of β-amyloid peptide oligomers in Alzheimer's disease

2016 ◽  
Vol 52 (57) ◽  
pp. 8865-8868 ◽  
Author(s):  
Guanglei Lv ◽  
Anyang Sun ◽  
Peng Wei ◽  
Ning Zhang ◽  
Haichuang Lan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescent Probe ◽  
Amyloid Peptide ◽  
Specific Detection ◽  
Aβ Oligomers ◽  
Β Amyloid ◽  
Β Amyloid Peptide

A fluorescent probe for the specific detection of Aβ oligomers in Alzheimer's disease both in vitro and in vivo was developed.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine

2020 ◽  
Vol 20 (13) ◽  
pp. 1214-1234 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Bijo Mathew ◽  
Pankoj Kumar Das ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Neutralizing Antibodies ◽  
Neurodegenerative Disorder ◽  
Symptomatic Relief ◽  
Aβ Oligomers ◽  
Th2 Immune Response ◽  
Age Related ◽  
Anti Inflammatory

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 507
Author(s):  
Rosaria Meccariello ◽  
Stefania D’Angelo
Keyword(s):  
Oxidative Stress ◽  
Food Sources ◽  
Preventive Action ◽  
Nutritional Interventions ◽  
Beneficial Effects ◽  
Age Related ◽  
Macromolecular Damage ◽  
And Oxidative Stress

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.

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