Drugs For Treatment Of Alzheimer's Disease Research Articles

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on EJMC-4e were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of 12o, which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over EJMC-4e. Molecular docking and dynamics studies revealed the binding sites and stability of the complex of 12o with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that 12o can easily cross the blood-brain barrier. Interestingly, 12o also expresses promising metal chelation activity, while EJMC-4e was found to be devoid of this property. Further, 12o inhibited metal-induced or self Aβ1-42 aggregation. Observing the neuroprotection ability of 12o against H2O2-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, 12o also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, 12o is able to effectively reduce mitochondrial and cellular oxidative stress in the AD Drosophila model. Finally, 12o could reverse memory impairment in the scopolamine-induced AD mice model, as evident through in vivo and ex vivo studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer's disease.

Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear. The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and AppNL-G-F (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR. DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD. The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.

Comparative Efficacy of Anti-Amyloid and Non-Antiamyloid Drugs for Treatment of Alzheimer’s Disease: A Network Meta-Analysis

BACKGROUND: Alzheimer’s disease is a degenerative neurological disorder that contributes 60-80% of all dementia cases, typically occurring at the age of 65 years. Currently available therapeutics for treatment are only capable of limiting the progression of cognitive decline. The focus of many Alzheimer’s disease drug therapies involves the hypothesized cause of pathogenesis in the disease, beta protein in the brain. Based on the Preferred Reporting Items for Meta-Analysis (PRISMA) for Network Meta-Analyses (NMA) framework, the present study was conducted to compare the efficacy of such drugs that target beta-amyloid directly or indirectly, with that of other treatments studied in randomized controlled trials. METHODS: Utilizing a network meta-analysis, direct and indirect comparisons between interventions could be done, providing a ranking of intervention in terms of efficacy in treating cognitive symptoms of Alzheimer’s disease. RESULTS: A total of 33 studies were included in four analyses of intervention trials that reported cognitive outcomes measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or Mini-Mental State Examination (MMSE) score. Based on the findings, anti-amyloid agents did not show a marked advantage over other therapies in improving cognitive scores. Results showed that parasympathomimetic agents were consistently ranked higher in terms of Surface Under the Cumulative Ranking (SUCRA) score, with anti-tau agents providing a possible superiority over all other interventions at improving MMSE scores for treatments lasting longer than 24 weeks. High-dose anti-amyloid therapies were effective at improving MMSE score in short term treatments lasting not more than 24 weeks but fall behind other drugs in longer durations. CONCLUSION: For better understanding on the choice of anti-amyloid and non-antiamyloid therapies, future well-designed large studies including safety outcome and cost- benefit analyses on the different interventions are recommended. Additionally, anti-tau therapies show a clearer potential over anti-amyloid therapies and should thus be given more focus in future drug research.  

Lead Compounds for Brain Protection against Alzheimer’s

To find a promising drug for treatment of Alzheimer’s` is not that easy target. Although some medications have FDA approval for management of AD, all of them offer symptomatic benefits. This is because efforts to find the treatment are distributed among many targets in the brain which make it so difficult to find a drug that can correct all of them at once. The primary histopathologic lesions of Alzheimer’s pathology are amyloid plaques, NFTs and neuronal loss with a wide genetic background which deteriorate the patient condition so rapidly. In the current article, we highlight some lead compounds that protect brain cells from undergoing this dark pathway or, which is more important, to stop deterioration and worsening of the case after starting of the disease. sex lead compounds of natural sources suggested as anti-AD drugs with brief discussion of each of them regarding its chemistry, physiochemical properties, mechanism of action, bioavailability, derivatives and method of synthesis. These natural extracts can be expected as lead compounds for design and synthesis of more effective derivatives as prophylactic treatment against Alzheimer’s. The aim of our review is to help to direct efforts to treat AD toward the prophylactic choice according to research results and scientific facts.

Novel chalcone derivatives of ursolic acid as acetylcholinesterase inhibitors: Synthesis, characterization, biological activity, ADME prediction, molecular docking and molecular dynamics studies

Acetylcholinesterase (AChE) is a critical target in the prevention of Alzheimer's Disease (AD) progression. With the goal of developing potential acetylcholinesterase inhibitors, a new series chalcone derivatives of ursolic acid (4–11) were synthesized and characterized by means of their NMR, FTIR and HRMS spectral data. hAChE inhibition abilities of all compounds were tested in vitro. Compounds 10, 8 and 7 showed high hAChE inhibitory potential with the IC50 values of 1.82, 4.65 and 5.36 µM respectively. When compared to the standard inhibitor (Galantamine, IC50= 1.96 µM), compound 10 was the most potent derivative. After performing kinetic studies, KM constant and Vmax value of hAChE were determined as 0.059 mM and 0.052 EU/ml respectively. Inhibition type of compound 10 was found as competitive and Ki constant was calculated as 1.31 ± 0.18 µM. The inhibition mechanism of compounds was predicted by molecular docking, MM/GBSA analysis, molecular dynamics simulation and ADME studies. Molecular docking studies showed that compounds 10, 8, and 7 have highest binding scores (-9.235, -8.827, -8.645 kcal/mol, respectively), while the standard inhibitor galantamine exhibited binding score of -5.106 kcal/mol. According to the MM/GBSA analysis, compounds 10 and 7 displayed binding free energies of -46.19 and -49.19 kcal/mol, respectively, which were higher than the standard's binding free energy of -41.82 kcal/mol. Molecular dynamic simulations were confirmed successful placement of the compounds 10, 8 and 7 in the active site of AChE. The in silico ADME predictions indicated that compound 10 has acceptable potency as a drug in treatment of AD.

Aldol-click generated silane: A turn-on fluorescent sensor for Al3+ ion and exploring its anti-Alzheimer activity via molecular docking

Alzheimer's disease (AD) is one of the leading neurodegenerative disorder whose cure is yet to be developed. Elevated levels of Aluminium ion and acetylcholinesterase in brain tissue are main concern for progression of AD. Hence, both detection of Aluminium ion and inhibition of acetylcholinesterase are important research areas that have gained attention. Aldol-generated chalcones and Click-derived triazoles are among the emerging privileged scaffolds for selective and sensitive detection of metal ions and as promising pharmacological drugs. The present work focuses on design and development of ‘chalcogenyl-based triazole coupled organosilane’ that could selectively detect neurotoxic Aluminium ion. The binding strength and ratio between the two was discovered from B–H plot and Job's plot method respectively from fluorescent studies. Further linear calibration curve was utilized to calculate the limit of detection (LOD). The possible binding site of chemosensor for Aluminium ion has been recognized from 1H NMR studies and DFT calculations. Molecular docking, a computational approach was used to scrutinize the synthesized ‘chalcogenyl based triazole coupled organosilane’ as whether it could inhibit the activity of acetylcholinesterase and thus be further examined as potent pharmacological drug in treatment of AD.

Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs.

Neuroprotective effects of novel compound FMDB on cognition, neurogenesis and apoptosis in APP/PS1 transgenic mouse model of Alzheimer's disease

Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer's disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound R-9-(4fluorophenyl)-3-methyl-10,10,-Hydrogen-6-hydrogen-benzopyran named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. 6 months old APP/PS1 transgenic mice were intragastrical administered with FMDB (1.25, 2.5 and 5 mg/kg) every other day for 8 weeks. LV-ERβ-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown estrogen receptor β (ERβ). We found that FMDB ameliorated cognitive impairment in the Morris water maze and novel object recognition tests, increased hippocampal neurogenesis and prevented hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERβ mediated CBP/p300, CREB and brain-derived neurotrophic factor (BDNF) signaling, and membrane ERβ mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Our study demonstrated the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.

Repurposing of phyto-ligand molecules from the honey bee products for Alzheimer's disease as novel inhibitors of BACE-1: small molecule bioinformatics strategies as amyloid-based therapy.

Alzheimer's disease (AD) is one of the neurodegenerative diseases, manifesting dementia, spatial disorientation, language, cognitive, and functional impairment, mainly affects the elderly population with a growing concern about the financial burden on society. Repurposing can improve the traditional progress of drug design applications and could speed up the identification of innovative remedies for AD. The pursuit of potent anti-BACE-1 drugs for AD treatment has become a pot boiler topic in the recent past and to instigate the design of novel improved inhibitors from the bee products. Drug-likeness characteristics (ADMET: absorption, distribution, metabolism, excretion, and toxicity), docking (AutoDock Vina), simulation (GROMACS), and free energy interaction (MM-PBSA, molecular mechanics Poisson-Boltzmann surface area) analyses were performed to identify the lead candidates from the bee products (500 bioactives from the honey, royal jelly, propolis, bee bread, bee wax, and bee venom) for Alzheimer's disease as novel inhibitors of BACE-1 (beta-site amyloid precursor protein cleaving enzyme (1) receptor using appropriate bioinformatics tools. Forty-four bioactive lead compounds were screened from the bee products through high throughput virtual screening on the basis of their pharmacokinetic and pharmacodynamics characteristics, showing favorable intestinal and oral absorption, bioavailability, blood brain barrier penetration, less skin permeability, and no inhibition of cytochrome P450 inhibitors. The docking score of the forty-four ligand molecules was found to be between -4 and -10.3 kcal/mol, respectively, exhibiting strong binding affinity to BACE1 receptor. The highest binding affinity was observed in the rutin (-10.3 kcal/mol), 3,4-dicaffeoylquinic acid (-9.5 kcal/mol), nemorosone (-9.5 kcal/mol), and luteolin (-8.9 kcal/mol). Furthermore, these compounds demonstrated high total binding energy -73.20 to -105.85 kJ/mol), and low root mean square deviation (0.194-0.202 nm), root mean square fluctuation (0.0985-0.1136 nm), radius of gyration (2.12 nm), number of H-bonds (0.778-5.436), and eigenvector values (2.39-3.54 nm2) in the molecular dynamic simulation, signifying restricted motion of Cα atoms, proper folding and flexibility, and highly stable with compact of the BACE1 receptor with the ligands. Docking and simulation studies concluded that rutin, 3,4-dicaffeoylquinic acid, nemorosone, and luteolin are plausibly used as novel inhibitors of BACE1 to combat AD, but further in-depth experimental investigations are warranted to prove these in silico findings.

Preparation of electrochemical sensor based on β-cyclodextrin/Carbon Nanotube Nanocomposite for Donepezil Hydrochloride as drug for treatment of Alzheimer's Disease

Preparation of electrochemical sensor based on β-cyclodextrin/Carbon Nanotube Nanocomposite for Donepezil Hydrochloride as drug for treatment of Alzheimer's Disease

Impact of Genetic Risk Factors for Alzheimer's Disease on Brain Glucose Metabolism.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 30 million people worldwide. Despite growing knowledge of AD pathophysiology, a complete understanding of the pathogenic mechanisms underpinning AD is lacking, and there is currently no cure for AD. Extant literature suggests that AD is a polygenic and multifactorial disease underscored by complex and dynamic pathogenic mechanisms. Despite extensive research and clinical trials, there has been a dearth of novel drugs for AD treatment on the market since memantine in 2003. This lack of therapeutic success has directed the entire research community to approach the disease from a different angle. In this review, we discuss growing evidence for the close link between altered glucose metabolism and AD pathogenesis by exploring how genetic risk factors for AD are associated with dysfunctional glucose metabolism. We also discuss modification of genes responsible for metabolic pathways implicated in AD pathology.

Preparation of Amyloid Fibrils Using Recombinant Technology.

Amyloid fibrils are widely investigated as they are directly associated with various neurodegenerative diseases. For example, a vast of experimental results have shown that the oligomeric and fibrillar aggregates of the amyloid β-peptide (Aβ) play a critical role in the pathogenesis of Alzheimer's disease (AD). Therefore, the accessibility of certain amounts of pure Aβ peptide is necessary for the studies of the mechanism of neurotoxicity. In this regard, recombinant methods provide the possibility to synthesize the Aβ peptide in vitro and thus promote the investigation of the relationship between peptide structure and pathogenic mechanism. These investigations further provide the fundamental supports for developing potential drugs for AD treatment. In addition to providing support for the study of pathogenic mechanisms, the recombination of Aβ peptides also offers the possibility to utilize these unique protein nanomaterials. For example, Aβ peptides tend to assemble into chiral amyloid fibrils with an ultra-high aspect ratio. These unique nano features, together with the inherent protein characteristics, of amyloid fibrils, allow them to be used in biomedical and environmental fields. Accordingly, herein, we aim to introduce the recombinant protocols for the synthesis of Aβ peptides. The experimental route to assemble these peptides to amyloid fibrils is also summarized in this chapter.

Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model.

Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

Hydroxypropyl Methylcellulose-Based Hydrogel Copolymeric for Controlled Delivery of Galantamine Hydrobromide in Dementia

The study aims to prepare a smart copolymeric for controlled delivery of Galantamine hydrobromide. The synthesis of the hydrogel was executed through free radical polymerization using HPMC (Hydroxypropyl methylcellulose) and pectin as polymers and acrylic acid as monomer. Cross-linking was performed by methylene bisacrylamide (MBA). HPMC-pectin-co-acrylic acid hydrogel was loaded with Galantamine hydrobromide (antidementia drug) as a model drug for treatment of Alzheimer based dementia. Formulated hydrogels (SN1–SN9) were characterized for Fourier transform-infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, and energy dispersive X-ray. Drug loading efficiency, gel fraction, measurements of porosity, and tensile strength were reported. Swelling and release studies were performed at pH 1.2 and 7.4. Drug liberation mechanism was evaluated by applying different release kinetic models. Galantamine hydrobromide was released from prepared hydrogels by Fickian release mechanism. Swelling, gel fraction, porosity, and drug release percentages were found to be dependent on hydroxypropyl methylcellulose, pectin, acrylic acid, and methylene bisacrylamide concentrations. By increasing HPMC amount, swelling was increased from 76.7% to 95.9%. Toxicity studies were conducted on albino male rabbits for a period of 14 days. Hematological and histopathological studies were carried out to evaluate safety level of hydrogel. Successfully prepared HPMC-pectin-co-acrylic acid hydrogel showed good swelling and release kinetics, which may help greatly in providing controlled release drug effect leading to enhanced patient compliance for dementia patients.

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer's Disease Treatment.

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps.

Vulnerability of the brain milieu to even the subtle changes in its normal physiology is guarded by a highly efficient blood brain barrier. A number of factors i.e. molecular weight of the drug, its route of administration, lipophilic character, etc. play a significant role in its sojourn through the Blood Brain Barrier (BBB) and limit the movement of drug into brain tissue through BBB. To overcome these problems, alternative routes of drug administration have been explored to target the drugs to brain tissue. Nasal route has been widely reported for the administration of drugs for treatment of Alzheimer. In this innovative approach, the challenge of BBB is bypassed. Through this route, both the larger as well as polar molecules can be made to reach the brain tissues. Generally, these systems are either pH dependent or temperature dependent. The present review highlights the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of nasal drug delivery system, nasal formulations of various drugs that have been tried for their nasal delivery for treatment of Alzheimer. It also dives deep to understand the factors that contribute to the success of such formulations to carve out a direction for this niche area to be explored further.

US, EU, and Japanese Regulatory Guidelines for Development of Drugs for Treatment of Alzheimer's Disease: Implications for Global Drug Development.

Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer’s disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.

The effect of terminal groups and halogenation of KLVFF peptide on its activity as an inhibitor of β-amyloid aggregation.

The aggregation of Aβ peptide into amyloid fibrils in the brain is associated with Alzheimer's disease (AD). Inhibition of Aβ aggregation seemed a potential treatment for AD. It was previously shown that a short fragment of Aβ peptide (KLVFF, 16-20) bound Aβ inhibited its aggregation. In this work, using KLVFF peptide, we synthesized two peptide families and then evaluated their inhibitory capacities by conventional assays such as thioflavin T (ThT) fluorescence spectroscopy, turbidity measurement, and the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). The effect of peptide terminal groups on its inhibitory activity was first studied. Subsequently, the influence of halogenated amino acids on peptide anti-aggregation properties was investigated. We found that iodinated peptide with amine in the N and amide in the C termini, respectively, was the best inhibitor of Aβ fibers formation. Halogenated peptides seemed to decrease the number of Aβ fibrils; however, they did not reduce Aβ cytotoxicity. The data obtained in this work seemed promising in developing potential peptide drugs for treatment of AD.

Organoplatinum-Substituted Polyoxometalate Inhibits β-amyloid Aggregation for Alzheimer's Therapy.

Aggregated β-amyloid (Aβ) is widely considered as a key factor in triggering progressive loss of neuronal function in Alzheimer's disease (AD), so targeting and inhibiting Aβ aggregation has been broadly recognized as an efficient therapeutic strategy for curing AD. Herein, we designed and prepared an organic platinum-substituted polyoxometalate, (Me4 N)3 [PW11 O40 (SiC3 H6 NH2 )2 PtCl2 ] (abbreviated as PtII -PW11 ) for inhibiting Aβ42 aggregation. The mechanism of inhibition on Aβ42 aggregation by PtII -PW11 was attributed to the multiple interactions of PtII -PW11 with Aβ42 including coordination interaction of Pt2+ in PtII -PW11 with amino group in Aβ42 , electrostatic attraction, hydrogen bonding and van der Waals force. In cell-based assay, PtII -PW11 displayed remarkable neuroprotective effect for Aβ42 aggregation-induced cytotoxicity, leading to increase of cell viability from 49 % to 67 % at a dosage of 8 μm. More importantly, the PtII -PW11 greatly reduced Aβ deposition and rescued memory loss in APP/PS1 transgenic AD model mice without noticeable cytotoxicity, demonstrating its potential as drugs for AD treatment.

Organoplatinum‐Substituted Polyoxometalate Inhibits β‐amyloid Aggregation for Alzheimer's Therapy

AbstractAggregated β‐amyloid (Aβ) is widely considered as a key factor in triggering progressive loss of neuronal function in Alzheimer's disease (AD), so targeting and inhibiting Aβ aggregation has been broadly recognized as an efficient therapeutic strategy for curing AD. Herein, we designed and prepared an organic platinum‐substituted polyoxometalate, (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2] (abbreviated as PtII‐PW11) for inhibiting Aβ42 aggregation. The mechanism of inhibition on Aβ42 aggregation by PtII‐PW11 was attributed to the multiple interactions of PtII‐PW11 with Aβ42 including coordination interaction of Pt2+ in PtII‐PW11 with amino group in Aβ42, electrostatic attraction, hydrogen bonding and van der Waals force. In cell‐based assay, PtII‐PW11 displayed remarkable neuroprotective effect for Aβ42 aggregation‐induced cytotoxicity, leading to increase of cell viability from 49 % to 67 % at a dosage of 8 μm. More importantly, the PtII‐PW11 greatly reduced Aβ deposition and rescued memory loss in APP/PS1 transgenic AD model mice without noticeable cytotoxicity, demonstrating its potential as drugs for AD treatment.