Alzheimer's Disease Drug Candidates Research Articles

Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?

IntroductionNeurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links. MethodsWe searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self-induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (-)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD. ResultsNeuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (-)-phenserine, and plasma-derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (-)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies. DiscussionThese findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD.

Inhibition of Butyrylcholinesterase with Fluorobenzylcymserine, An Experimental Alzheimer's Drug Candidate: Validation of Enzoinformatics Results by Classical and Innovative Enzyme Kinetic Analyses.

Selective butyrylcholinesterase (BuChE)-inhibition, increases acetylcholine (ACh) levels. In rodents, this inhibition is known to boost cognition. Also, this occurs without the typical unwanted adverse effects of acetylcholinesterase-inhibitors or AChE-Is. The novel compound, fluorobenzylcymserine (FBC), is derived from our effort to design a selective BuChE-inhibitor. Also, we wanted to check whether butyrylcholinesterase-inhibitors (BuChE-Is) possessed an edge over AChE-Is in Alzheimer's disease (AD) in terms of efficacy and/or tolerance. FBC was synthesized as reported earlier while enzymatic activity of BuChE was calculated by Ellman-technique. Molecular docking was performed using Autodock4.2. We applied classical as well as innovative analyses of enzyme-kinetics for exploring "FBC:human BuChE-interaction". The mode of inhibition and kinetic parameters were also determined. Docking results displayed two strong interacting sites for FBC. One of these binding sites was previously identified as a deep narrow groove having polar aromatic residues while a second site was identified during this study which displayed better interaction and was lined with aliphatic and sulphur containing residues. At low concentrations of BuChE, the IC50 was found to be very low i.e. 4.79 and 6.10 nM for 12 and 36 µg, respectively, whereas it increased exponentially by increasing the units of BuChE. These analyses indicate that FBC is an interesting AD drug candidate that could provide a potent and partial mixed type of inhibition of human BuChE.

Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

Acetylcholinesterase (AChE) plays an important role in Alzheimer's disease (AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, anti-AChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic (MD) simulations; and absorption, distribution, metabolism, and excretion (ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of −12.335 with a good binding energy value of −73.313kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies.

Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain.

Age is, by far, the greatest risk factor for Alzheimer's disease (AD), yet few AD drug candidates have been generated that target pathways specifically associated with the aging process itself. Two ubiquitous features of the aging brain are the intracellular accumulation of aggregated proteins and inflammation. As intraneuronal amyloid protein is detected before markers of inflammation, we argue that old, age-associated, aggregated proteins in neurons can induce inflammation, resulting in multiple forms of brain toxicities. The consequence is the increased risk of old, age-associated, neurodegenerative diseases. As most of these diseases are associated with the accumulation of aggregated proteins, it is possible that any therapeutic that reduces intracellular protein aggregation will benefit all.-Currais, A., Fischer, W., Maher, P., Schubert, D. Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain.

In vitro monitoring of amyloid β-peptide oligomerization by Electrospray differential mobility analysis: An alternative tool to evaluate Alzheimer's disease drug candidates

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein aggregation, like more than twenty other human pathologies. One major protein incriminated in AD is the 42-residue amyloid-β peptide (Aβ1–42) which aggregates to form neurotoxic oligomers and fibrils. While, low molecular weight oligomers have been evidenced as neurotoxic species, only scarce methods raise the challenge to monitor the beginning of the aggregation process, called oligomerization. We propose here an innovative and fast monitoring of the time-dependent Aβ1–42 oligomerization pattern by electrospray differential mobility analysis (ES-DMA). We developed a non-denaturing method based on ES-DMA to afford a real-time and direct characterization of the early, metastable and neurotoxic species. This technique provided their size distribution over time. At the beginning of the in vitro oligomerization process of Aβ1–42, the size distribution is characterized by two populations with modal diameters around 3.5 and 4nm, corresponding to Monomer and Small oligomers. After few hours, larger species around 10nm are observed. The results were correlated to those obtained by capillary electrophoresis. We also demonstrated the ability of our method to evaluate Aβ1–42 kinetics modulators. Thereby, ES-DMA provides new insights on Aβ1–42 oligomerization in the presence of sugar-based peptidomimetic analogs which were recently described as modulators of Aβ1–42 self-assembly and neurotoxicity inhibitors.

Anti-arrhythmic Medication Propafenone a Potential Drug for Alzheimer's Disease Inhibiting Aggregation of Aβ: In Silico and in Vitro Studies.

Alzheimer's disease (AD) is the most common form of dementia caused by the formation of Aβ aggregates. So far, no effective medicine for the treatment of AD is available. Many efforts have been made to find effective medicine to cope with AD. Curcumin is a drug candidate for AD, being a potent anti-amyloidogenic compound, but the results of clinical trials for it were either negative or inclusive. In the present study, we took advantages from accumulated knowledge about curcumin and have screened out four compounds that have chemical and structural similarity with curcumin more than 80% from all FDA-approved oral drugs. Using all-atom molecular dynamics simulation and the free energy perturbation method we showed that among predicted compounds anti-arrhythmic medication propafenone shows the best anti-amyloidogenic activity. The in vitro experiment further revealed that it can inhibit Aβ aggregation and protect cells against Aβ induced cytotoxicity to almost the same extent as curcumin. Our results suggest that propafenone may be a potent drug for the treatment of Alzheimer's disease.

Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery

IntroductionNeurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. MethodsThe neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis. ResultsThe best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays. DiscussionThe combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.

Pharmacokinetic Properties of a Novel D-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers.

It has been shown that amyloidβ (Aβ) oligomers play an important role in the pathology of Alzheimer's disease (AD). D3, a peptide consisting solely of D-enantiomeric amino acid residues, was developed to specifically eliminate Aβ oligomers and is therapeutically active in transgenic AD mice. D-peptides have several advantages over L-peptides, but little is known about their pharmacokinetic potential in vivo. Here, we analysed the pharmacokinetic properties of RD2, a rationally designed and potent D3 derivative. The pharmacokinetic analysis was performed using (3)H-RD2 after administration via several routes in mice. The time dependent amount of radiolabelled RD2 was measured in plasma and several organ homogenates by liquid scintillation counting. Furthermore, binding to plasma proteins was estimated. RD2 penetrates into the brain, where it is thought to implement its therapeutic function. All administration routes result in a maximal brain concentration per dose (Cmax/D) of 0.06 (μg/g)/(mg/kg) with brain/plasma ratios ranging between 0.7 and 1.0. RD2 shows a small elimination constant and a long terminal half-life in plasma of more than 2days. It also exhibits high bioavailability after i.p., s.c. or p.o. administration. These excellent pharmacokinetic properties confirm that RD2 is a very promising drug candidate for AD.

Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.

Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells. To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L). Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures. Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay. As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels. This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.

Humanin: A Possible Linkage Between Alzheimer’s Disease and Type 2 Diabetes

The prevalence of Alzheimer's disease (AD) is higher among type 2 diabetes mellitus (T2DM) patients. In T2DM patients, the progression of AD is more rapid. Furthermore, several pathophysiological pathways are common to AD and T2DM. Humanin is a recently introduced, mitochondrial-derived peptide with neuroprotective effects. Humanin can alter the mechanisms involved in AD and T2DM pathogenesis. Insulin resistance as well as oxidative stress has been shown to be associated with increased amyloid deposition in brain neurons and islet beta cells. Moreover, advanced glycation end products and lipid metabolism disorders are common pathways of oxidative stress and low-grade systemic inflammation in AD and T2DM. These common pathways may explain AD and T2DM pathogenesis and suggest common treatments for both diseases. Treatments for T2DM and AD attempt to slow cognitive decline, and recent investigations have focused on agents that may alter pathways common to AD and T2DM pathogenesis. Non-steroidal antiinflammatory drugs, such as interleukin-1 antagonists and statins, are possible drug candidates for both AD and T2DM.

Determination of tacrine‐6‐ferulic acid in rat plasma by LC‐MS/MS and its application to pharmacokinetics study

Tacrine, as a drug for treating Alzheimer's disease (AD), has low efficacy owing to its single function and serious side effects. However, tacrine-6-ferulic acid (T6FA), the dimer which added ferulic acid to tacrine, has been found to be a promising multifunctional drug candidate for AD and much more potent and selective on acetylcholinesterase (AChE) than tacrine. The aim of the present work was to develop and validate an LC-MS/MS method with electrospray ionization for the quantification of T6FA in rat plasma using tacrine-3-ferulic acid (T3FA) as internal standard and to examine its application for pharmacokinetic study in rats. Following a single liquid-liquid extraction with ethyl acetate, chromatographic separation was achieved at 25 °C on a BDS Hypersil C18 column with a mobile phase composed of 1% formic acid and methonal (30:70, v/v) at a flow rate of 0.2 mL/min. Quantification was achieved by monitoring the selected ions at m/z 474.2 → 298.1 for T6FA and m/z 432.2 → 199.0 for T3FA. The method was validated to be rapid, specific, accurate and precise over the concentration range of 0.5-1000.0 ng/mL in rat samples. Furthermore, it was successfully applied for the pharmacokinetic measurement of T6FA with an oral administration at 40 mg/kg to rats.

FRET-Based Calcium Imaging: A Tool for High-Throughput/Content Phenotypic Drug Screening in Alzheimer Disease

Perturbed intracellular store calcium homeostasis is suggested to play a major role in the pathophysiology of Alzheimer disease (AD). A number of mechanisms have been suggested to underlie the impairment of endoplasmic reticulum calcium homeostasis associated with familial AD-linked presenilin 1 mutations (FAD-PS1). Without aiming at specifically targeting any of those pathophysiological mechanisms in particular, we rather performed a high-throughput phenotypic screen to identify compounds that can reverse the exaggerated agonist-evoked endoplasmic reticulum calcium release phenotype in HEK293 cells expressing FAD-PS1. For that purpose, we developed a fully automated high-throughput calcium imaging assay using a fluorescence resonance energy transfer–based calcium indicator at single-cell resolution. This novel robust assay offers a number of advantages compared with the conventional calcium measurement screening technologies. The assay was employed in a large-scale screen with a library of diverse compounds comprising 20,000 low-molecular-weight molecules, which resulted in the identification of 52 primary hits and 4 lead structures. In a secondary assay, several hits were found to alter the amyloid β (Aβ) production. In view of the recent failure of AD drug candidates identified by target-based approaches, such a phenotypic drug discovery paradigm may present an attractive alternative for the identification of novel AD therapeutics.

Akt-activated GSK3β inhibitory peptide effectively blocks tau phosphorylation

Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Abnormal overexpression of GSK3β has been implicated in tau hyperphosphorylation, thus many GSK3β inhibitors have been developed as drug candidates for AD. However, the potent GSK3β inhibitors are prone to show side effects because they can interfere with basal GSK3β function. We have recently reported that the specific motifs in the Wnt coreceptor LRP6 are able to directly inhibit GSK3β when phosphorylated, an thus a novel GSK3β inhibitory peptide (GIP) that can be activated by Akt, was generated by combining the LRP6 motif and an Akt target sequence. In the present study, we tested the effects of a novel GIP on modulating tau phosphorylation and tauopathy. The GSK3β-inhibitory action of GIP was tested ex vivo using hippocampal brain tissue. Human neuroblastoma SH-SY5Y cells were used to determine the protective effects of GIP against Aβ-induced death and tau phosphorylation. We used 3xTg-AD mice to verify the effect of GIP on the tau hyperphosphorylation and Aβ plaques in vivo. GIP effectively blocked GSK3 β -induced tau phosphorylation in hippocampal homogenate. In addition, the GIP fused with a cell permeable sequence attenuated Aβ-induced tau phosphorylation and cell death in human neuroblastoma cells. Interestingly, high Akt activation was observed particularly in the hippocampus assuming that GIP can be activated to inhibit GSK3 β. T he designed GIP significantly reduced tau phosphorylation in the hippocampus of 3 ' Tg-AD mice without affecting levels of Aβ plaques. In conclusion, the current findings provide a novel concept for the drug development targeting tau hyperphosphorylation in AD, and GIP may have potential as a therapeutic drug in tauopathies.

Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, &amp;#945; -Synuclein Synthesis, Interleukin-1&amp;#946; Release, and Cholinergic Action.

A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβ levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.

Potential repurposing of oncology drugs for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, affecting about 30 million people worldwide. Despite recent advances in understanding its molecular pathology, no mechanism-based drugs are currently available that can halt the progression of AD. Because amyloid-β-peptide (Aβ), a primary component of senile plaques, is thought to be a central pathogenic culprit, several disease-modifying therapies are being developed, including inhibitors of Aβ-producing proteases and immunotherapies with anti-Aβ antibodies. Drug repositioning or repurposing is regarded as a complementary and reasonable approach to identify new drug candidates for AD. This commentary will discuss the clinical relevance of an attractive candidate compound reported in a recent paper by Hayes et al. (BMC Medicine 2013) as well as perspectives regarding the possible repositioning of oncology drugs for the treatment of AD.See related research article here http://www.biomedcentral.com/1741-7015/11/81

Exploring the multifunctionality of thioflavin- and deferiprone-based molecules as acetylcholinesterase inhibitors for potential application in Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of people worldwide. With no prevention or cure available, this progressive disease has a significant impact on society - dementia patients and their caretakers, healthcare systems, and the economy. Previously, we have reported initial developments of multifunctional drug candidates for AD based on two scaffolds - thioflavin-T and deferiprone. Individually, these molecules have shown several favorable functionalities, including dissociation of toxic amyloid-β aggregates, antioxidant and/or metal chelating ability that can pacify reactive oxygen species, plaque targeting, and blood-brain barrier penetration. In this work, the two scaffolds are augmented with a new functionality - acetylcholinesterase inhibition. This functionality is incorporated by derivatization with a carbamate group, which is the active group in some AD drugs currently in the market. We present the rationale for designing three novel compounds, their synthesis and characterization, including X-ray crystallographic data, and encouraging results from in vitro and computational acetylcholinesterase inhibition studies. Also, we evaluate the compounds as potential drug candidates by Lipinski's rules and cytotoxicity studies in a neuronal cell line. Overall, we demonstrate the feasibility of improving on two well established scaffolds, as well as show in vitro efficacy plus initial mode of action and biological compatibility data.

Involvement of GSK3 and PP2A in ginsenoside Rb1's attenuation of aluminum-induced tau hyperphosphorylation

Environmental agent aluminum, a well-known neurotoxin, has been proposed to play a role in the development of Alzheimer's disease (AD), and produced clinical and pathological features which were strikingly similar to those seen in AD brain, such as neurofibrillary tangles. Ginsenoside Rb1, highly abundant active component of ginseng, has been demonstrated to be neuroprotective against various neurotoxins. In this study we investigated the effect of Rb1 on aluminum-induced tau hyperphosphorylation in ICR mice. Mice were exposed to aluminum chloride (200mg/kg/day) for 6 months followed by a post treatment of Rb1 (20mg/kg/day) for another 4 months. Aluminum exposure induced the cognitive ability by Morris water maze, and upregulated the tau phosphorylation level at Ser396 accompanied by increasing p-GSK and decreasing PP2A level in motor, sensory cortex and hippocampal formation. Post treatment of Rb1 significantly improved the learning and memory and reduced the tau phosphorylation by reversing the p-GSK3 and PP2A level. Our results indicate that ginsenoside Rb1 protected mice against Al-induced toxicity. The possible mechanism may be its role in preventing tau hyperphosphorylation by regulating p-GSK3 and PP2A level, which implicate Rb1 as the potential preventive drug candidate for AD and other tau pathology-related neuronal degenerative diseases.

Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer, Inhibits Amyloid-β-Mediated Alzheimer's Disease-Associated Pathogenesis In Vitro and In Vivo

We have previously synthesized a series of hybrid compounds by linking ferulic acid to tacrine as multifunctional agents based on the hypotheses that Alzheimer's disease (AD) generates cholinergic deficiency and oxidative stress. Interestingly, we found that they may have potential pharmacological activities for treating AD. Here we report for the first time that tacrine-6-ferulic acid (T6FA), one of these compounds, can prevent amyloid-β peptide (Aβ)-induced AD-associated pathological changes in vitro and in vivo. Our results showed that T6FA significantly inhibited auto- and acetylcholinesterase (AChE)-induced aggregation of Aβ1–40 in vitro and blocked the cell death induced by Aβ1–40 in PC12 cells. In an AD mouse model by the intracerebroventricular injection of Aβ1–40, T6FA significantly improved the cognitive ability along with increasing choline acetyltransferase and superoxide dismutase activity, decreasing AChE activity and malondialdehyde level. Based on our findings, we conclude that T6FA may be a promising multifunctional drug candidate for AD.

Protective effects of ginsenoside Rd against okadaic acid-induced neurotoxicity in vivo and in vitro

Ethnopharmacological relevancePanax ginseng, a traditional Chinese herbal medicine, has been widely used to restore the disease and enhance the healthy body in Asia for about 5000 years. The present study aimed to investigate the possible neuroprotective effects of ginsenoside Rd against OA-induced toxicity. Materials and methodsGinsenoside Rd was used in tauopahy models of Alzheimer's disease (AD). To mimic the in vivo or in vitro tau hyperphosphorylation, okadaic acid (OA), a protein phosphatase inhibitor, was bilaterally micro-infused into the cerebral ventricle of adult male Sprague-Dawley (SD) rats, or added in media of cultured cortical neurons. The phosphorylation levels of tau and the activities of protein phosphatase 2A (PP-2A) were measured and compared with ginsenoside Rd pretreated groups. ResultsPretreatment with ginsenoside Rd in SD rats (10mg/kg for 7 days) or in cultured cortical neurons (2.5 or 5μmol/L for 12h) reduced OA-induced neurotoxicity and tau hyperphosphorylation by enhancing the activities of PP-2A. ConclusionsThe result of the present work implied that ginsenoside Rd protected SD rats and cultured cortical neurons against OA-induced toxicity. The possible neuroprotective mechanism may be that ginsenoside Rd decreases OA-induced the hyperphosphorylation of tau by the increase in activities of PP-2A. Thus, this study promises that ginsenoside Rd might be a potential preventive drug candidate for AD and other tau pathology-related neuronal degenerative diseases.

Alzheimer's Disease Drug Candidates Stabilize A- β Protein Native Structure by Interacting with the Hydrophobic Core

Deposition of amyloid fibrils, consisting primarily of A β 40 and A β 42 peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of A β peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the A β 42 monomer at its α-helical conformation and a pentamer fibril fragment of A β 42 peptide with or without LRL and fluorene series compounds to investigate the mechanism of inhibition. The results show that the active drug candidates, LRL22 (EC 50 = 0.734 μM) and K162 (EC 50 = 0.080 μM), stabilize hydrophobic core I of A β 42 peptide (residues 17–21) to its α-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC 50 > 10 μM) and K182 (EC 50 > 5 μM), have little to no similar effect. This explains the different behavior of the drug candidates in experiments. Of more importance, this phenomenon indicates that hydrophobic core I of the A β 42 peptide plays a major mechanistic role in the formation of amyloid fibrils, and paves the way for the development of new drugs against AD.