Alzheimer's Disease Drug Research Articles

Molecular Insights on the Modulated Acetylcholinesterase Inhibition Activity of Tacrine Adsorbed on Biocompatible Graphene Oxide

AbstractGraphene oxide (GO) based nano‐formulation has gained much attention because of its carbonaceous composition with biologically benign properties. In this study, the interactions of GO with tacrine (TAC), an FDA approved Alzheimer's disease (AD) drug, are explored using various analytical tools and theoretical modeling techniques. Furthermore, the modulatory effect of these nano‐conjugates toward the in‐vitro catalytic activity of the neurodegenerative enzyme acetylcholinesterase (AChE) is also quantified. The maximal rate for enzyme inhibition in presence of the nanoconjugate decreases up to an extent of 16 and 34 % in comparison with TAC and GO, respectively. Interestingly, these results are in sharp contrast to the increased AChE activity on adsorption into spherical gold and silver nanoparticles. The current findings demonstrate the synergistic use of TAC−GO hybrid material with augmented AChE inhibition efficacy towards the treatment of Alzheimer's disease (AD). Additionally, GO presents a sustainable alternative for biomedical applications to inorganic equivalents.

Aβ Oligomer Toxicity-Reducing Therapy for the Prevention of Alzheimer’s Disease: Importance of the Nrf2 and PPARγ Pathways

Recent studies have revealed that soluble amyloid-β oligomers (AβOs) play a pathogenetic role in Alzheimer’s disease (AD). Indeed, AβOs induce neurotoxic and synaptotoxic effects and are also critically involved in neuroinflammation. Oxidative stress appears to be a crucial event underlying these pathological effects of AβOs. From a therapeutic standpoint, new drugs for AD designed to remove AβOs or inhibit the formation of AβOs are currently being developed. However, it is also worth considering strategies for preventing AβO toxicity itself. In particular, small molecules with AβO toxicity-reducing activity have potential as drug candidates. Among such small molecules, those that can enhance Nrf2 and/or PPARγ activity can effectively inhibit AβO toxicity. In this review, I summarize studies on the small molecules that counteract AβO toxicity and are capable of activating Nrf2 and/or PPARγ. I also discuss how these interrelated pathways are involved in the mechanisms by which these small molecules prevent AβO-induced neurotoxicity and neuroinflammation. I propose that AβO toxicity-reducing therapy, designated ATR-T, could be a beneficial, complementary strategy for the prevention and treatment of AD.

Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains

Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with AβELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.

STOP-AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease.

We propose an unbiased methodology to rank compounds for advancement into comprehensive preclinical testing for Alzheimer's disease (AD). Translation of compounds to the clinic in AD has been hampered by poor predictive validity of models, compounds with limited pharmaceutical properties, and studies that lack rigor. To overcome this, MODEL-AD's Preclinical Testing Core developed a standardized pipeline for assessing efficacy in AD mouse models. We hypothesize that rank-ordering compounds based upon pharmacokinetic, efficacy, and toxicity properties in preclinical models will enhance successful translation to the clinic. Previously compound selection was based solely on physiochemical properties, with arbitrary cutoff limits, making ranking challenging. Since no gold standard exists for systematic prioritization, validating a selection criteria has remained elusive. The STOP-AD framework evaluates the drug-like properties to rank compounds for in vivo studies, and uses an unbiased approach that overcomes the validation limitation by performing Monte-Carlo simulations. HIGHLIGHTS: Promising preclinical studies for AD drugs have not translated to clinical success. Systematic assessment of AD drug candidates may increase clinical translatability. We describe a well-defined framework for compound selection with clear selection metrics.

Real-Time Observation for Dynamic Oscillation during the Self-Assembly and Clearance of Aβ42.

The dynamic oscillation implicated in structural heterogeneity during the self-assembly of amyloid peptide 1-42 (Aβ42) may play a crucial role in eliciting cellular responses. We developed a real-time monitoring platform to observe an oscillatory non-equilibrium interaction that dominated the Aβ42 clearance by neuronal cells during interplay with an oscillator (lipopolysaccharide, LPS). Molecular dynamics studies indicated that the electrostatic and hydrophobic segments of LPS involved in the temporary heteromolecular association and slightly decelerated the intrinsic thermally-induced protein dynamics of Aβ42. A bait-specific intervention strategy could temporarily slow down the self-propagation of Aβ42 to extend the lifetime of autonomous oscillation and augment the Aβ42 clearance of neuronal cells. The lifetime increment of dynamic oscillation shows a bait concentration-dependent manner to reflect the non-equilibrium binding strength. This relationship may serve as a drug-screening predictor for Alzheimer's disease drug discovery.

An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of neurons, followed by synaptic impairment. Since the discovery of AD, substantial factual research has surfaced that outlines the disease's causes, molecular mechanisms, and prospective therapeutics, but a successful cure for the disease has not yet been discovered. This may be attributed to the complicated pathogenesis of AD, the absence of a well-defined molecular mechanism, and the constrained diagnostic resources and treatment options. To address the aforementioned challenges, extensive disease modeling is essential to fully comprehend the underlying mechanisms of AD, making it easier to design and develop effective treatment strategies. Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. Moreover, the critical risk factors associated with AD including genetics, aging, environmental variables, lifestyle habits, medical conditions, viral/bacterial infections, and psychiatric factors have been summarized. The present study will entice researchers to more thoroughly comprehend and explore the current status of the molecular mechanism of AD, which may assist in AD drug development in the forthcoming era.

Multi-Targeting Neuroprotective Effects of Syzygium aromaticum Bud Extracts and Their Key Phytocompounds against Neurodegenerative Diseases.

Alzheimer's disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aβ) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a range of side effects and are not able to cover different aspects of the disease. Therefore, finding a safer therapeutic approach that can affect multiple targets at a time is highly desirable. In the present study, the underlying neuroprotective mechanism of an important culinary spice, Syzygium aromaticum (Clove) extract, and major bioactive compounds were studied in hydrogen peroxide-induced oxidative stress in human neuroblastoma SH-SY5Y cell lines as a model. The extracts were subjected to GC-MS to identify important bioactive components. The extracts and key bio-actives reduced reactive oxygen species (ROS), restored mitochondrial membrane potential (MMP), and provided neuroprotection from H2O2-induced oxidative stress in cell-based assays due to the antioxidant action. They also reduced lipid peroxidation significantly and restored GSH content. Clove extracts have also displayed anti-acetylcholinesterase (AChE) activity, anti-glycation potential, and Aβ aggregation/fibrilization inhibition. The multitarget neuroprotective approach displayed by Clove makes it a potential candidate for AD drug development.

Thiadiazole - A promising structure in design and development of anti-Alzheimer agents.

The design and development of effective multitargeted agents in treating Alzheimer disease (AD) has always been a hot topic in the field of drug discovery. Since AD is a multifactorial disorder, various key hidden players such as deficit of acetylcholine (ACh), tau-protein aggregation, and oxidative stress have been associated with the incidence and progress of AD. In pursuit of improving efficacy and expanding the range of pharmacological activities of current AD drugs, the molecular hybridization method is also used intensively. Five-membered heterocyclic systems such as thiadiazole scaffolds have previously been shown to have therapeutic activity. Thiadiazole analogs as an anti-oxidant compound have been known to include a wide range of biological activity from anti-cancer to anti-Alzheimer properties. The suitable pharmacokinetic and physicochemical properties of the thiadiazole scaffold have introduced it as a therapeutic target in medicinal chemistry. The current review portrays the critical role of the thiadiazole scaffold in the design of various compounds with potential effects in the treatment of Alzheimer's disease. Furthermore, the rationale used behind hybrid-based design strategies and the outcomes achieved through the hybridization of Thiadiazole analogs with various core structures have been discussed. In addition, the data in the present review may help researchers in the design of new multidrug combinations that may provide new options for the treatment of AD.

C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies.

Protein phosphatase 2A (PP2A) is an important Ser/Thr phosphatase that participates in the regulation of multiple cellular processes. This implies that any deficient activity of PP2A is the responsible of severe pathologies. For instance, one of the main histopathological features of Alzheimer's disease is neurofibrillary tangles, which are mainly comprised by hyperphosphorylated forms of tau protein. This altered rate of tau phosphorylation has been correlated with PP2A depression AD patients. With the goal of preventing PP2A inactivation in neurodegeneration scenarios, we have aimed to design, synthesize and evaluate new ligands of PP2A capable of preventing its inhibition. To achieve this goal, the new PP2A ligands present structural similarities with the central fragment C19-C27 of the well-established PP2A inhibitor okadaic acid (OA). Indeed, this central moiety of OA does not exert inhibitory actions. Hence, these compounds lack PP2A-inhibiting structural motifs but, in contrast, compete with PP2A inhibitors, thus recovering phosphatase activity. Proving this hypothesis, most compounds showed a good neuroprotective profile in neurodegeneration models related to PP2A impairment, highlighting derivative 10, named ITH12711, as the most promising one. This compound (1) restored in vitro and cellular PP2A catalytic activity, measured on a phospho-peptide substrate and by western-blot analyses, (2) proved good brain penetration measured by PAMPA, and (3) prevented LPS-induced memory impairment of mice in the object recognition test. Thus, the promising outcomes of the compound 10 validate our rational approach to design new PP2A-activating drugs based on OA central fragment.

Analysis of Potential Cinnamomum zeylanicum Blume Essential Oil Against Alzheimer’s Disease: A Molecular Docking Study

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder with progressive impairment of behavioural and cognitive functions and the most common cause of dementia. The pathophysiology of AD is associated with low acetylcholine, accumulation of amyloid beta plaque, and neurofibrillary tangles in the brain. Cinnamomum zeylanicum is known to have many medicinal properties, especially neuroprotective effects. Objective: This research was designed to determine the neuroprotective potential of the phytochemicals C. zeylanicum using an in silico study. Methods: There are 5 phytochemicals compounds of C. zeylanicum used in this study. It's qualified for Lipinski’s rules of five and can cross blood brain barrier. The protein targets were AChE, BACE1, and GSK-3. Molecular docking and visualization were performed using Avogadro, AutoDock 4.2 PyMol and Biovia Discovery Studio 2019. Results: In silico results show that the main phytochemical compounds of C. zeylanicum Blume essential oil have great potency as an AD drug. The best interaction model of the compound was shown by trans-cinnamyl acetate and coumaric acid. Although the binding energy of the compounds is lower than AD drugs (donepezil, rivastigmine, galantamine), the binding energy is not much different from rivastigmine and galantamine. Conclusion: The phytochemical compounds of C. zeylanicum Blume essential oil have an effect as a neuroprotective agent for AD and should be investigated in future research.

A Drug for Alzheimer's Disease: Aducanumab

Alzheimer's disease (AD) is a problem that has plagued humans for a long time. About 24.3 million people have Alzheimer's disease in the world, and the number is growing at a rate of 4.6 million new patients each year. The prevalence of AD increases with age. As a result, the issue of AD has become increasingly negative in recent years. The purpose of the paper is to examine whether the marketed aducanumab is useful in the treatment of AD and to compare it with several other drugs commonly used to treat AD. This paper will discuss the effectiveness and adverse effects of common medications for AD treatment and why aducanumab has not been effective in treating AD and how to improve the effectiveness of aducanumab for AD patients in the future. In addition, this paper will analyze whether aducanumab is marketed because of commercial considerations or because the drug itself was fully compliant with FDA requirements

Preliminary In Vitro and In Vivo Insights of In Silico Candidate Repurposed Drugs for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aβ40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.

The Cost Burden of Alzheimer’s Disease on Care Partners (P14-6.004)

<h3>Objective:</h3> To conduct a systematic literature review (SLR) assessing the economic impact of Alzheimer’s disease (AD), with an emphasis on care partners and disease progression. <h3>Background:</h3> AD significantly impacts care partners. <h3>Design/Methods:</h3> A protocol was developed before searches in PubMed, Embase, and PsycINFO were run in November 2021 via the Silvi.ai-platform. SLR conduct followed standard guidelines. Eligible studies were in English and provided data from January 2011–November 2021. <h3>Results:</h3> Of 1043 hits, 25 studies were relevant for data extraction. AD costs were defined heterogeneously between studies; however, most studies included AD and non-AD drugs and out- and in-patient visits. Seven studies specifically explored the cost burden of AD for care partners: hours needed to support the partner, loss of work productivity, and implications for future employability. Monthly caretaking cost was similar across studies and countries, varying between €6435–€10503 for mild AD in Germany and Spain, €8045– €13295 for moderate AD in France and Germany, and €15154–€23765 for severe AD in the UK and Germany. The major cost driver was clinical status severity of the patient. Few studies reported care partner work impairment. One study comparing matched care versus non-care partners demonstrated significantly higher activity impairment (25.4% vs. 21.8%) and greater absenteeism (5.4% vs. 3.1%), presenteeism-related impairment (22.7% vs. 18.4%), and overall work impairment (25.8% vs. 20.4%). An increase in work impairment with AD severity was seen across countries (US, Japan, and EU5). <h3>Conclusions:</h3> Most studies focused on the cost burden on society or patients. In seven studies reporting cost impact on care partners, cost burden was similar across countries and health care systems. Cost impact on care partners increased from early to severe AD, particularly for work impairment. More research is needed to identify the true cost burden for care partners. <b>Disclosure:</b> Mrs. Hviid Hahn-Pedersen has stock in Novo Nordisk. Mr. Solís-Tarazona has received personal compensation for serving as an employee of Novo Nordisk A/S. The institution of Prof. Holm-Larsen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Novo Nordisk.

Effect of Amyloid PET on Clinical Management of Alzheimer’s Disease Medication Therapy: The Khatib Study (P11-6.009)

<h3>Objective:</h3> Evaluate the role of amyloid-beta PET scans as a diagnostic tool in clinical settings and its influence on patient care management with respect to Alzheimer’s disease drug therapy. <h3>Background:</h3> The NIA-AA 2018 guidelines for clinical research define Alzheimer’s disease (AD) on a biological basis, requiring the presence of amyloid deposition in the brain. This framework helps to more precisely define the processes underlying cognitive impairment, and is particularly poignant given the advent of amyloid-beta PET scans which allow the visualization of amyloid-beta in vivo. It is unclear how this framework may lead to changes in management of patients, particularly in an ethnically and culturally diverse location such as in South Florida. <h3>Design/Methods:</h3> We included 102 cognitively impaired patients from the multi-site Khatib Study (mean age 77+/−7 years, 45% women, 15% Hispanic). Patients were evaluated for AD drug therapy (cholinesterase inhibitors and memantine) before and after amyloid-beta PET scan by neurologists. The probabilities of change in AD drug therapy by amyloid-beta PET scan results were estimated using Wilson intervals for binomial proportions and tested using the McNemar test. <h3>Results:</h3> For amyloid PET positive patients (n=68), the use of AD drug therapy increased significantly (<i>p</i>&lt;.05), from 78% (95%CI [67,86]) to 91% (95% CI [82,96]). A total of 15% (95%CI [8,25]) started AD drug therapy and 2% (95%CI [0.3,8]) stopped AD drug therapy. For amyloid PET negative patients (n=34), the use of AD drug therapy decreased significantly (<i>p</i>&lt;.05), from 76% (95%CI [60,88]) to 53% (95%CI [37,69]). A total of 29% (95%CI [17,46]) stopped AD drug therapy and 6% (95%CI [2,19]) started AD drug therapy. <h3>Conclusions:</h3> Clinical confirmation of patients’ amyloid PET status resulted in increases in prescribed AD drug therapy for amyloid positive patients and decreases in the amyloid negative patients. This study highlights the significant bidirectional influence of amyloid PET scans on patient care management. <b>Disclosure:</b> Ms. Ariko has nothing to disclose. Miss Modjeski has nothing to disclose. Dr. Chang has nothing to disclose. Ms. Merrifield has received personal compensation for serving as an employee of The Council on Aging of Martin County - The Kane Center. Ms. Ripper has received personal compensation for serving as an employee of the council on aging of Martin County Inc. Mrs. Clark Dowd has nothing to disclose. James Galvin has nothing to disclose. Dr. Camargo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Camargo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GE Health. The institution of Dr. Camargo has received research support from American Academy of Neurology.

Expression, purification and micelle reconstruction of the transmembrane domain of the human amyloid precursor protein for NMR studies

The multiple-step cleavage of amyloid precursor protein (APP) generates amyloid-β peptides (Aβ), highly toxic molecules causing Alzheimer's disease (AD). The nonspecific cleavage between the transmembrane region of APP (APPTM) and γ-secretase is the key step of Aβ generation. Reconstituting APPTM under physiologically-relevant conditions is crucial to investigate how it interacts with γ-secretase and for future AD drug discovery. Although producing recombinant APPTM was reported before, the large scale purification was hindered by the use of biological protease in the presence of membrane protein. Here, we expressed recombinant APPTM in Escherichia coli using the pMM-LR6 vector and recovered the fusion protein from inclusion bodies. By combining Ni-NTA chromatography, cyanogen bromide cleavage, and reverse phase high performance liquid chromatography (RP-HPLC), isotopically-labeled APPTM was obtained in high yield and high purity. The reconstitution of APPTM into dodecylphosphocholine (DPC) micelle generated mono dispersed 2D 15N-1H HSQC spectra in high quality. We successfully established an efficient and reliable method for the expression, purification and reconstruction of APPTM, which may facilitate future investigation of APPTM and its complex in more native like membrane mimetics such as bicelle and nanodiscs.

Microbiota-gut-brain axis and related therapeutics in Alzheimer's disease: prospects for multitherapy and inflammation control.

Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota-gut-brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do notimprove AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose ofthis review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. "MGBA-based multitherapy" is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient's condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. "MGBA-based multitherapy" offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.

Identification of Novel Compounds Inhibiting the Kinase Activity of the CDK5/p25 Complex via Direct Binding to p25.

Tamoxifen, the gold standard drug for endocrine therapy for breast cancer, modulates the phosphorylation status of the TAU protein in Alzheimer's disease by inhibiting CDK5 kinase activity. Its binding to p25 prevents CDK5/p25 complexation and hence a decrease of CDK5 activity. In breast tumors, this complex is involved in the proliferation and survival of cancer cells, as well as in the disease's prognosis. Still, the molecular stability of the CDK5/p25 complex following tamoxifen exposure in this cancer type has not yet been clearly deciphered. Here, we report the functional characterization of CDK5 and its p25 regulatory subunit in the absence and presence of tamoxifen. In addition, two novel inhibitors of the kinase activity of the CDK5/p25 complex are identified, both of which would reduce the risk of recurrence of estrogen receptor-positive (ER+) breast cancers and prevent drawbacks induced by tamoxifen exposure. Accordingly, 6His-CDK5 and 6His-p25 have been expressed and purified. Fluorescence anisotropy measurements have been used to assess that the two proteins do form an active complex, and thermodynamic parameters of their interaction were measured. It was also confirmed that tamoxifen directly binds to p25 and inhibits CDK5 kinase activity. Similar observations were obtained using 4-hydroxytamoxifen, an active metabolized form of tamoxifen. Two novel compounds have been identified here that harbor a benzofuran moiety and were shown to target directly p25, and their bindings resulted in decreased CDK5 kinase activity. This encouraging alternative opens the way to the ensuing chemical optimization of this scaffold. It also promises a more specific therapeutic approach that may both tackle the pathological signaling in breast cancer and provide a potential new drug for Alzheimer's disease.

Five-mer peptides prevent short-term spatial memory deficits in Aβ25-35-induced Alzheimer’s model mouse by suppressing Aβ25-35 aggregation and resolving its aggregate form

BackgroundThe development of drugs for Alzheimer’s disease (AD), which is related to the misfolding and aggregation of amyloid-β (Aβ), is high in demand due to the growing number of AD patients. In this study, we screened 22 kinds of 5-mer synthetic peptides derived from the Box A region of Tob1 protein to find a peptide effective against Aβ aggregation.MethodsA Thioflavin T (ThT) assay was performed to evaluate aggregation and screen aggregation inhibitors. Male ICR mice (6 weeks old) were administered saline, 9 nmol Aβ25-35, or a mixture of 9 nmol Aβ25-35 and 9 nmol GSGFK in the right lateral ventricle. Short-term spatial memory was assessed through Y-maze. Microglia cells (BV-)2 cells were plated on 24-well plates (4 × 104 cells/well) and incubated for 48 h, and then, the cells were treated with 0.01, 0.05, 0.1, 0.2, or 0.5 mM GSGFK. After incubation for 24 h, bead uptake was evaluated using a laser confocal microscope and Cytation 5.ResultsWe found two kinds of peptides, GSGNR and GSGFK, that were not only suppressed by aggregation of Aβ25-35 but also resolved the aggregated Aβ25-35. Results obtained from the Y-maze test on an Aβ25-35-induced AD model mouse indicated that GSGFK prevents the deficits in short-term memory induced by Aβ25-35. The effect of GSGFK on phagocytosis in BV-2 cells proved that GSGFK activates the phagocytic ability of microglia.ConclusionsIn conclusion, 5-mer peptides prevent short-term memory deficit in Aβ25-35 induced AD model mouse by reducing the aggregated Aβ25-35. They may also upregulate the phagocytic ability of microglia, which makes 5-mer peptides suitable candidates as therapeutic drugs against AD.

Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics.

Two anti-amyloid monoclonal antibodies (MABs)-lecanemab (Leqembi®) and aducanumab (Aduhelm®)-have been approved in the USA for the treatment of Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies are the first disease-modifying therapies for AD that achieve slowing of clinical decline by intervening in the basic biological processes of the disease. These are breakthrough agents that can slow the inevitable progression of AD into more severe cognitive impairment. The results of trials of anti-amyloid MABs support the amyloid hypothesis and amyloid as a target for AD drug development. The success of MABs reflects a relentless application of neuroscience knowledge to solving major challenges facing humankind. The success of these transformative agents will foster the development of more anti-amyloid MABs, other types of anti-amyloid therapies, treatments of other targets of AD biology, and new approaches to therapies for an array of neurodegenerative disorders. Monoclonal antibodies have side effects and, during the period of treatment initiation, patients must be closely monitored for the occurrence of amyloid-related imaging abnormalities (ARIA) and infusion reactions. A successful first step in the development of disease-modifying therapy for AD defines desirable features for the next phase of therapeutic development including less frequent ARIA, more convenient administration, and greater efficacy. Unprecedented agents make new demands on patients and care partners, clinicians, payers, and health care systems. Collaboration among stakeholders is essential to take advantage of the therapeutic benefits offered by these agents and to make them widely available. Monoclonal antibodies usher in a new era in AD therapy and define a new landscape of what is possible for therapeutic development for neurodegenerative disorders.

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.