Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Alzheimer′s disease using network pharma⁃cology approach and in vitro experimental validation

OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

Advances in Drug Therapy for Alzheimer’s Disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Effect of cerebralcare granule®combined with donepezil on Alzheimer’s disease

Background:The current prevalence of Alzheimer’s disease(AD)in the elderly has risen from 1%at 65 to 40%to 50%at 95,and the overall proportion is rising.Emerging evidence suggests that ros-driven oxidative stress is a crucial mediator of the aging process.Thus,in recent years,oxidative damage and inflammation have become targets for exploring pharmacological strategies for treating age-related diseases.Methods:In C57BL/6J mice,to determine whether the mechanism of action of cerebralcare granule®(CG)combined with donepezil(Don)treatment is better than dementia alone,we constructed a mouse model and treated it with CG in combination with Don.Results:A combination of Don and CG significantly reduces the damage caused by lipid peroxidation in the hippocampus of AD mice,reduces oxidative damage,and reduces inflammation,increases the activity of antioxidant enzymes,which is finally manifested as the improvement effect on the learning and memory impairment of AD mice.Conclusion:CG combined with Don has a better effect on improving cognitive and behavioral deficits caused by D-galactose in AD mice than Don alone.The mechanism may be related to reducing inflammation via the NF-κB pathway,resisting oxidative damage and increasing acetylcholine levels.

Liposome based drug delivery as a potential treatment option for Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.

Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease

Alzheimer’s disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer’s disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer’s disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer’s disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer’s disease or slow down its progression, and they should enter clinical trials as soon as possible.

An innovative approach for the treatment of Alzheimer's disease: the role of peroxisome proliferator-activated receptors and their ligands in development of alternative therapeutic interventions

Alzheimer＇s disease is a multifactorial pathology, for which no cure is currently available. Nowadays, researchers are moving towards a new hypothesis of the onset of the illness, linking it to a metabolic impairment, q-his innovative approach will lead to the identification of new targets for the preparation of new effective drugs. Peroxisome proliferator-activated receptors and their ligands are the ideal candidates to reach the necessary breakthrough to defeat this complicate disease.

Nose-to-brain drug delivery approach：a key to easily accessing the brain for the treatment of Alzheimer＇s disease

Alzheimer＇s disease（AD）：AD,a neurodegenerative disorder and a significant cause of dementia throughout the world mostly affects the older adults but sometimes also seen in young age（early state AD）（Agrawal et al.,2017）.

Current status and future prospects of stem cell therapy in Alzheimer’s disease

Alzheimer’s disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer’s disease, and the current state of stem cell transplantation in the treatment of Alzheimer’s disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer’s disease.

Modulating balance of synaptic and extrasynaptic NMDA receptors as strategy for Alzheimer disease drug discovery

The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.

Confirmation of the Experimentally-Proven Therapeutic Utility of Madecassoside in an Aβ_1-42Infusion Rat Model of Alzheimer’s Disease by in Silico Analyses

The accumulation of amyloid β peptide 1 - 42 (Aβ1-42) in the brain of Alzheimer’s disease (AD) patients is known to be associated with neurodegeneration and memory impairment. More recently, we reported that madecassoside, an active component of Centella asiatica, improved memory impairment in an Aβ1-42 infusion rat model of AD, ameliorated neurotoxicity in SH-SY5Y cells, and inhibited in vitro Aβ1-42 fibril formation. In the present study, we investigated the utility of in silico analyses in corroborating observed in vivo and in vitro effects of madecassoside in AD to further assess the therapeutic benefits of madecassoside. The 3D structure of Aβ1-42 was downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The binding of madecassoside to Aβ1-42 was assessed by molecular docking. The chemical structure of madecassoside was modeled and converted to the PDB format. Madecassoside was found to successfully dock with Aβ1-42. Computational demonstration of the binding of madecassoside to Aβ1-42 further corroborated the inhibitory effect of madecassoside on Aβ1-42 fibrillogenesis which was demonstrated in our previous study. These data showed the potential utility of madecassoside as a preventive medication in Aβ1-42-induced neurodegenerative diseases such as AD.

Computational Analyses of Docosahexaenoic Acid (DHA, C22:6, n-3) with Alzheimer’s Disease-Causing Amyloid Peptide Aβ1-42 Reassures Its Therapeutic Utility

The accumulation of amyloid β peptide1-42 (Aβ1-42) masses in the brains of Alzheimer’s Disease (AD) patients is associated with neuronal loss and memory deficits. We have previously reported that oral administration of docosahexaenoic acid (DHA, C22:6, n-3) significantly decreases Aβ burden in the brains of AD model rats and that direct in vitro incubation of DHA with Aβ1-42 curbs the progression of amyloid fibrillation. In the present in silico study, we investigated whether DHA computationally binds with amyloid peptides. The NMR solution structures of Aβ1-42 were downloaded from the Protein Data Bank (PDB IDs: 1Z0Q and 2BEG). The binding of DHA to Aβ peptides was assessed by molecular docking using both a flexible and rigid docking system. Thioflavin T (ThT) was used as positive control. The chemical structures of ThT and DHA were modeled and converted to the PDB format using PRODRUG. Drug-like properties of DHA were evaluated by ADME (Absorption, Distribution, Metabolism, and Excretion). DHA was found to successfully dock with Aβ1-42. Computational analyses of the binding of DHA to Aβ1-42, as evaluated by docking studies, further corroborated the inhibitory effect of DHA on in vitro Aβ1-42 fibrillogenesis and might explain the in vivo reduction of amyloid burden observed in the brains of DHA-administered AD model rats demonstrated in our previous study. These computational data suggest the potential utility of DHA as a preventive medication in Aβ-induced neurodegenerative diseases, including AD.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.

Advances in the study of Alzheimer's disease

Alzheimer＇ s disease （AD） is the most common cause of dementia, and the only treatment currently available for the disease is acetylcholinesterase inhibitors. Recent progress in understanding the molecular and cellular pathophysiology of Alzheimer＇s disease has suggested possible pharmacological interventions, including acetylcholineseterase inhibitors; secretase inhibitors; cholesterol lowering drugs; metal chelators and amyloid immunization. The objective of this paper is to review the main drugs possibly used for AD and their future therapeutic effects.

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

Etiological factors of Alzheimer disease and recent advances of its treatment

OBJECTIVE： To investigate the etiological factors of Alzheimer disease （AD） and the advance in drug treatment. DATA SOURCES： Using the terms ＂Alzheimer disease, etiology, drug treatment＂, we searched Medline database for AD treatment-related English literatures which were published between January 1993 and September 2006. Other literatures were obtained by searching concrete magazines and papers by hand. STUDY SELECTION： The data were selected primarily. Epidemiologic study and randomized controlled clinical trials were selected, and those studies with repetitive or similar contents were excluded. DATA EXTRACTION： Totally 1 537 AD and its treatment-related literatures were collected, and 32 of them were involved. Altogether 1 505 non-randomized controlled clinical trials, repetitive studies and reviews were excluded. DATA SYNTHESIS： The restriction of curative effect is a progressive neural degenerative disease. Although the etiological hypothesis of this disease has been introduced, the etiological factors of this disease are still unclear. The current treatments mainly involve： preventing against A 13 formation and clearing A 13, application of antioxidant and free radical scavengers, application of anti-inflammatory preparation, application of cholinergic preparation, hormonal therapy, application of metabolic enhancer, application of neurotrophic factor and nerve protectant, gene therapy and so on. CONCLUSION： The etiological factors of AD are still unclear, and symptomatic treatment is much taken in clinical therapy. Therefore, the curative effects of AD are still not very ideal.

Cure for Alzheimer’s Disease

Alzheimer’s disease (AD) is progressively being recognized amongst the most vital medical and social issues in older individuals in industrialized and non-industrialized countries. To date, just symptomatic medications exist for this disease, all attempting to offset the neurotransmitter disturbance.?Recently, cholinesterase inhibitors (CIs) are now accessible and have been authorized for the treatment of mild to moderate AD. Further remedial alternative available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments equipped for halting or slightly adjusting the course of AD are known as “ailment changing” medications, and are still under extensive examination. To obstruct the movement of the ailment, they need to interfere with the pathogenic steps in charge of the clinical symptoms, including the disposition of extracellular amyloid?β?plaques and intracellular neurofibrillary tangle formation, irritation, oxidative damage, iron deregulation and cholesterol metabolism. This paper discusses the cure for Alzheimer’s disease, the current symptomatic treatments and the treatment of mild and moderate Alzheimer’s disease and the functions of its drugs.

Analysis of Technological Developments in the Treatment of Alzheimer’s Disease through Patent Documents

Population aging and the consequent change in the profile of the age pyramid are already a reality the world over. One undeniable effect of this aging process is the significant increase in the number of people with Alzheimer’s disease (AD), which is the most common form of dementia, accounting for around 50% - 60% of all cases. AD tends to affect people in their 60 s, becoming progressively more commonplace in older age groups. It is an incurable disease, and patients can live for many years taking medication on a daily basis. This study shows that research into AD is on the rise around the world because the pharmaceutical industry and research institutions are seeking new types of drugs to treat and even cure Alzheimer’s patients. By analyzing patent documents, we map out the potential future treatments for this disease, indicating the leading countries and drugs companies that have invested most in a bid to accelerate progress towards new discoveries about the disease and the development of new drugs.

Hypertension and Alzheimer’s disease

Alzheimer’s disease （AD） accounts for 60% to 80% of dementia cases and is the most common cause of dementia. In the past decade, studies have shown a close association between blood pressure and AD. It is found that elevated blood pressure at midlife would in-crease the risk of dementia, including AD. However, there is nodefnitive conclusion about the relationship between elderly blood pressure and cognitive function. Abnormal pulse pressure may also increase the risk of dementia. The impact of antihypertensive drugs is inconclusive, and the mechanism of their protection of cognitive function is not clear.

Strategizing the Development of Alzheimer’s Therapeutics

Alzheimer’s Disease is a complex, progressive condition with symptoms that do not reveal themselves until significant changes to neuronal morphology have already occurred. The delayed manifestation of cognitive decline makes determination of the true etiological origins difficult. As a result, identification of ideal drug targets becomes seemingly impossible. The existing treatments for Alzheimer’s Disease may temporarily suppress the rate of cognitive decline, but do little to slow or halt neuronal decay. While many believe that the current approaches to identifying a cure for the disease are too narrow-minded, focusing heavily on the physical manifestations of the diseased brain such as amyloid plaques and neurofibrillary tangles, this review asserts the status of Alzheimer’s research as rational and multi-faceted.