s-allylcysteine and Alzheimer-Disease

Alzheimer's disease (AD) is the most common form of dementia in the older people and 7(th) leading cause of death in the United States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However, these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effective drugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a specific 'Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.

Topics: Alzheimer Disease; Cysteine; Garlic; Humans; Inflammation; Nerve Degeneration; Plant Extracts

Apolipoprotein E4 (ApoE) is a major genetic factor for developing Alzheimer's disease (AD). It plays a vital role in brain to maintain a constant supply of neuronal lipids for rapid and dynamic membrane synthesis. Aggregation of beta amyloid plaques (Aβ) and neurofibrillary tangles in brain are responsible for onset of AD. The current study is designed to predict a drug against over activity of apoE4. 22 natural compounds (marine, microorganism and plant derivative) were used in current study.. These compounds were used as inhibitors to target apoE4 protein activity. Moreover, six synthetic compounds were docked with target protein to compare and analyze the docking results with natural compounds. S-Allyl-L-Cysteine, Epicatechin Gallate and Fulvic acid showed highest binding affinity (-7.1, - 7 and -7 kcal /mol respectively). Analysis of the docked complex showed that Epicatechin Gallate bonded with Gln156 and Asp35. Furthermore, Fulvic Acid showed hydrogen bonding with Glu27. Among synthetic compound, Tideglusib had highest binding affinity with target protein but did not show hydrogen bonding with any amino acid residue. Moreover, a natural compound S-Allyl-LCysteine also showed highest binding affinity but did not show hydrogen bonding with any amino acid residue.. Our study highlighted Epicatechin Gallate as a potential lead compound on the basis of binding affinity and hydrogen bonding to inhibit the progression of AD.

Topics: Alzheimer Disease; Apolipoprotein E4; Benzopyrans; Biological Products; Catechin; Computer Simulation; Cysteine; Humans; Molecular Docking Simulation; Protein Interaction Domains and Motifs

Oxidative and nitrosative stress resulting in mitochondrial dysfunction are an early event in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid-2-related factor 2 (Nrf2) is a key transcription factor and regulator of the cellular response to oxidative stress. Thus known Nrf2 activators from food materials were tested for improvement of mitochondrial membrane potential (MMP) and ATP level in neuronal pheochromocytoma cell (PC12) models of oxidative and nitrosative stress. The effects of rotenone and sodium nitroprusside (complex inhibitors of the respiratory chain) on mitochondrial function were also studied. Furthermore, Nrf2 activators were tested in human embryonic kidney cells bearing the Swedish mutation of amyloid precursor protein (APP(sw) HEK cells) as a cellular model of familial AD. Preincubation with S-allyl-l-cysteine and isoliquiritigenin increased MMP in both PC12 cell models in a similar range as the positive control l-sulforaphane. None of the test compounds, however, improved MMP and ATP level in APP(sw) HEK cells.

Topics: Aging; Alzheimer Disease; Animals; Chalcones; Cysteine; Humans; Mitochondria; Oxidation-Reduction; Oxidative Stress; Rats

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. In AD patients, β-amyloid peptide (Aβ) plaques and neurofibrillary tangles are common features observed in the CNS. Aβ deposition results in the production of reactive oxygen species (ROS) leading to the hyperphosphorylation of tau that are associated with neuronal damage. Cholinesterase inhibitors and a partial NMDA receptor antagonist (memantine) have been identified as potential treatment options for AD. However, clinical studies have found that these drugs fail to prevent the disease progression. From ancient times, garlic (Allium sativum) has been used to treat several diseases. By 'aging' of garlic, some adverse reactions of garlic can be eliminated. Recent findings suggest that 'aged garlic extract' (AGE) may be a therapeutic agent for AD because of its antioxidant and Aβ lowering properties. To date, the molecular properties of AGE have been sparsely studied in vitro or in vivo. The present study tested specific biochemical and molecular effects of AGE in neuronal and AD rodent models. Furthermore, we identified S-allyl-L-cysteine (SAC) as one of the most active chemicals responsible for the AGE-mediated effect(s). We observed significant neuroprotective and neurorescue properties of AGE and one of its ingredients, SAC, from ROS (H(2)O(2))-mediated insults to neuronal cells. Treatment of AGE and SAC were found to protect neuronal cells when they were independently co-treated with ROS. Furthermore, a novel neuropreservation effect of AGE was detected in that pre-treatment with AGE alone protected ∼ 80% neuronal cells from ROS-mediated damage. AGE was also found to preserve pre-synaptic protein synaptosomal associated protein of 25 kDa (SNAP25) from ROS-mediated insult. For example, treatment with 2% AGE containing diet and SAC (20 mg/kg of diet) independently increased (∼70%) levels of SNAP25 and synaptophysin in Alzheimer's amyloid precursor protein-transgenic mice, of which the latter was significantly decreased in AD. Taken together, the neuroprotective, including preservation of pre-synaptic proteins by AGE and SAC can be utilized in future drug development in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cell Line, Transformed; Cysteine; Disease Models, Animal; Exploratory Behavior; Garlic; Gene Expression Regulation; Humans; Hydrogen Peroxide; L-Lactate Dehydrogenase; Memory, Short-Term; Mice; Mice, Transgenic; Neurons; Neuroprostanes; Plant Extracts; Rats; Reactive Oxygen Species; Synapses; Synaptophysin; Synaptosomal-Associated Protein 25; Time Factors

S-allyl cysteine (SAC), a sulfur containing amino acid derived from garlic, has been reported to have antioxidant, anti-cancer, antihepatotoxic and neurotrophic activity. This study was designed to examine the pre-treatment effects of SAC on cognitive deficits and oxidative damage in the hippocampus of intracerebroventricular streptozotocin (ICV-STZ)-infused mice. Mice pre-treated with SAC (30mg/kg) and vehicle (intraperitoneal; once daily for 15days) were bilaterally injected with ICV-STZ (2.57mg/kg body weight), whereas sham rats received the same volume of vehicle. The pre-treatment of this drug to Swiss albino mice has prevented the cognitive and neurobehavioral impairments. An increased latency and path length were observed in lesion, i.e. streptozotocin (STZ) group as compared to sham group and these were protected significantly in STZ group pre-treated with SAC. Levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) were decreased in STZ group as compared to sham group and pre-treatment of STZ group with SAC has protected their activities significantly. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS) in STZ group was attenuated significantly in SAC pre-treated group when compared with STZ lesioned group. Apoptotic parameters like DNA fragmentation, expression of Bcl2 and p53 were protected by the pre-treatment of SAC against STZ induced cognitive impairment. This study concludes that intervention of SAC could prevent free radicals associated deterioration of cognitive functions and neurobehavioral activities.

Topics: Alzheimer Disease; Animals; Antioxidants; Apoptosis; Cysteine; Disease Models, Animal; Immunohistochemistry; Injections, Intraventricular; Maze Learning; Mice; Nerve Degeneration; Neurotoxins; Oxidative Stress; Streptozocin

The neuroprotective effects of s-allyl cysteine, s-ethyl cysteine, and s-propyl cysteine in D-galactose (DG)-treated mice were examined. DG treatment increased the formation of Aβ(1-40) and Aβ(1-42), enhanced mRNA expression of β-amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1), and reduced neprilysin expression in brain (P < 0.05); however, the intake of three test compounds significantly decreased the production of Aβ(1-40) and Aβ(1-42) and suppressed the expression of APP and BACE1 (P < 0.05). DG treatments declined brain protein kinase C (PKC) activity and mRNA expression (P < 0.05). Intake of test compounds significantly retained PKC activity, and the expression of PKC-α and PKC-γ (P < 0.05). DG treatments elevated brain activity and mRNA expression of aldose reductase (AR) and sorbitol dehydrogenase as well as increased brain levels of carboxymethyllysine (CML), pentosidine, sorbitol, and fructose (P < 0.05). Test compounds significantly lowered AR activity, AR expression, and CML and pentosidine levels (P < 0.05). DG treatments also significantly increased the formation of reactive oxygen species (ROS) and protein carbonyl and decreased the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (P < 0.05); however, the intake of test compounds in DG-treated mice significantly decreased ROS and protein carbonyl levels and restored brain GPX, SOD, and catalase activities (P < 0.05). These findings support that these compounds via their anti-Aβ, antiglycative, and antioxidative effects were potent agents against the progression of neurodegenerative disorders such as Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cysteine; Disease Models, Animal; Galactose; Glycosylation; Humans; Male; Mice; Mice, Inbred C57BL; Oxidative Stress

Alzheimer's disease involves Abeta accumulation, oxidative damage and inflammation and there is currently no clinically accepted treatment to stop its progression. Its risk is known to reduce with increased consumption of antioxidant and anti-inflammatory agents. Fibrillar aggregates of Abeta are major constituents of the senile plaques found in the brains of AD patients and have been related to AD neurotoxicity. It is reported that SAC (S-allyl-l-cysteine), a water-soluble organosulfur component present in garlic is known to prevent cognitive decline by protecting neurons from Abeta induced neuronal apoptosis. Hence, we investigated the effects of SAC on Abeta aggregation by employing Thioflavin-T, transmission electron microscopy, SDS-PAGE, size exclusion-HPLC. Under aggregating conditions in vitro, SAC dose-dependently inhibited Abeta fibrillation and also destabilized preformed Abeta fibrils. Further, Circular dichroism and fluorescence quenching studies supported the binding ability of SAC to Abeta and inducing a partially folded conformation in Abeta. The 3D structure of Abeta-SAC complex was also predicted employing automated docking studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzothiazoles; Cysteine; Humans; Macromolecular Substances; Microscopy, Electron, Transmission; Neuroprotective Agents; Protein Binding; Protein Conformation; Protein Folding; Thiazoles

Multiple components present in garlic and various garlic preparations are known to exert pleiotropic protective effects as demonstrated in various in vitro and in vivo model systems. However, garlic pleiotropy in relation to Alzheimer's pathophysiology has not been explored extensively. Current study investigated anti-amyloidogenic, anti-inflammatory and anti-tangle effects of dietary aged garlic extract (AGE) (2%) and compared with its prominent constituents, i.e. S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS) (20 mg/kg) in Alzheimer's Swedish double mutant mouse model (Tg2576). Possible cholesterol-dependent and cholesterol-independent mechanisms of actions of AGE, SAC and DADS in exerting anti-amyloidogenic, anti-inflammatory and anti-tangle effects are discussed. Finally, ameliorative effects of dietary interventions were found to be in the order of AGE>SAC>DADS. If validated pre-clinically, dietary intervention with herbal alternative such as AGE having pleiotropic useful properties and least adverse effects may provide greater therapeutic benefit over a single-ingredient synthetic pharmaceutical drug having serious side effects in treating Alzheimer's disease.

Topics: Allyl Compounds; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blotting, Western; Brain; Cysteine; Disease Models, Animal; Disulfides; Enzyme-Linked Immunosorbent Assay; Female; Garlic; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Phosphorylation; Plant Extracts; Protein Processing, Post-Translational; tau Proteins

Neuronal apoptosis is one of the pathological features of Alzheimer's disease (AD) and is associated with senile plaques containing amyloid-b peptide (Abeta). Reactive oxygen species (ROS) are proposed to be involved in the apoptotic mechanism of Abeta-mediated neurotoxicity. The purpose of this study was to determine the effects of aged garlic extract (AGE) and S-allyl cysteine (SAC) on Abeta(25-35)-induced apoptosis and ROS generation in a rat pheochromocytoma (PC12) cell line.. PC12 cells were grown in RPMI 1640 medium containing 5% fetal calf serum and 10% horse serum. Cells were incubated with AGE or SAC for 24 h prior to exposure to Abeta(25-35) for various times. Cell viability, DNA fragmentation, number of apoptotic cells, caspase activity and generation of ROS were determined.. Abeta(25-35)-induced apoptosis in PC12 cells was demonstrated by: 1) A dose-dependent loss of cell viability; 2) A time- and dose-dependent increase in apoptotic cells; 3) An induction of DNA fragmentation; and 4) An increase in caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). After exposing PC12 cells to Abbeta(25-35), a significant increase in ROS preceded apoptotic events. AGE and SAC not only suppressed the generation of ROS but also attenuated caspase-3 activation, DNA fragmentation, PARP cleavage and eventually protected against Ab-induced apoptosis.. Our data suggest that ROS may be involved in Ab-induced apoptosis in PC12 cells. They further suggest that garlic compounds can reduce apoptosis, possibly by enhancing the endogenous antioxidant defenses.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Caspase 3; Caspases; Cell Survival; Cysteine; DNA Fragmentation; Enzyme Activation; Garlic; Humans; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Peptide Fragments; Plant Extracts; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proteins; Rats; Reactive Oxygen Species