Therapeutic Potential For Alzheimer's Disease Research Articles

Exploring the protective effect and molecular mechanism of betulin in Alzheimer's disease based on network pharmacology, molecular docking and experimental validation.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs learning and memory, with high rates of mortality. Birch bark has been traditionally used in the treatment of various skin ailments. Betulin (BT) is a key compound of birch bark that exhibits diverse pharmacological benefits and therapeutic potential in AD. However, the therapeutic effects and molecular mechanisms of BT in AD remain unclear. The present study aimed to predict the potential therapeutic targets of BT in the treatment of AD, and to determine the specific underlying molecular mechanisms through network pharmacology analysis and experimental validation. PharmMapper was used to predict the target genes of BT, and four disease databases were searched to screen for AD targets. The intersection targets were identified using the jveen website. Drug‑disease target protein‑protein interaction networks and hub genes were obtained and visualized using the Search Tool for the Retrieval of Interacting Genes/Proteins database and Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and AutoDock was used for molecular docking analysis of BT and hub genes. Subsequently, the network‑predicted mechanisms of BT in AD were verified in vitro. A total of 495 BT and 1,386 AD targets were identified, and 120 were identified as potential targets of BT in the treatment of AD. The results of the molecular docking analysis revealed a strong binding affinity between BT and the hub genes. In addition, enrichment analyses of GO and KEGG pathways indicated that the neuroprotective effects of BT mainly involved the 'PI3K‑Akt signaling pathway'. The results of in vitro experiments demonstrated that pretreatment with BT for 2 h may ameliorate formaldehyde (FA)‑induced cytotoxicity and morphological changes in HT22 cells, and decrease FA‑induced Tau hyperphosphorylation and reactive oxygen species levels. Furthermore, the PI3K/AKT signaling pathway was activated and the expression levels of downstream proteins, namely GSK3β, Bcl‑2 and Bax, were modified following pre‑treatment with BT. Overall, the results of network pharmacology and in vitro analyses revealed that BT may reduce FA‑induced AD‑like pathology by modulating the PI3K/AKT signaling pathway, highlighting it as a potential multi‑target drug for the treatment of AD.

Destabilisation of Alzheimer's amyloid-β protofibrils by Baicalein: mechanistic insights from all-atom molecular dynamics simulations.

Alzheimer's disease (AD) is the most common form of dementia and the fifth leading cause of death globally. Aggregation and deposition of neurotoxic Aβ fibrils in the neural tissues of the brain is a key hallmark in AD pathogenesis. Destabilisation studies of the amyloid-peptide by various natural molecules are highly relevant due to their neuroprotective and therapeutic potential for AD. We performed molecular dynamics (MD) simulation to investigate the destabilisation mechanism of amyloidogenic protofilament intermediate by Baicalein (BCL), a naturally occurring flavonoid. We found that the BCL molecule formed strong hydrophobic contacts with non-polar residues, specifically F19, A21, V24, and I32 of Chain A and B of the pentameric protofibril. Upon binding, it competed with the native hydrophobic contacts of the Aβ protein. BCL loosened the tight packing of the hydrophobic core by disrupting the hydrogen bonds and the prominent D23-K28 inter-chain salt bridges of the protofibril. The decrease in the structural stability of Aβ protofibrils was confirmed by the increased RMSD, radius of gyration, solvent accessible surface area (SASA), and reduced β-sheet content. PCA indicated that the presence of the BCL molecule intensified protofibril motions, particularly affecting residues in Chain A and B regions. Our findings propose that BCL would be a potent destabiliser of Aβ protofilament, and may be considered as a therapeutic agent in treating AD.

Herbal medicines in Alzheimer's disease and the involvement of gut microbiota.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. It severely affects the quality of life of victims. The prevalence of AD has been increasing in recent years. Therefore, it is of great importance to elucidate the pathogenic mechanism of AD and search for effective therapeutic approaches. Gut microbiota dysbiosis, an altered state of gut microbiota, has been well known for its involvement in the pathogenesis of AD. Much effort has been made in searching for approaches capable of modulating the composition of gut microbiota in recent years. Herbal medicines have attracted extensive attention in recent decades for the prevention and treatment of AD. Here, we gave an overview of the recent research progress on the modulatory effects of herbal medicines and herbal formulae on gut microbiota as well as the possible beneficial effects on AD, which may provide new insights into the discovery of anti-AD agents and their therapeutic potential for AD through modulating the composition of gut microbiota.

Identifying potential Alzheimer's disease therapeutics through GSK-3β inhibition: A molecular docking and dynamics approach

Emerging as a promising drug target for Alzheimer's disease (AD) therapy, glycogen synthase kinase 3β (GSK-3β) has garnered attention. This study sought to rigorously scrutinize a compendium of natural compounds retrieved from the ZINC database through pharmacodynamic experiments, employing a 1 H-indazole-3-carboxamide (INDZ) scaffold, to identify compounds capable of inhibiting the GSK-3β protein. Utilizing a multi-step approach, the study involved pharmacophore analysis, followed by molecular docking to select five promising ligands for further investigation. Subsequently, ESMACS simulations were employed to assess the stability of the ligand-protein interactions. Evaluation of the binding modes and free energy of the ligands revealed that five compounds (2a-6a) exhibited crucial interactions with the active site residues. Furthermore, various methodologies, including hydrogen bond and clustering analyses, were utilized to ascertain their inhibitory potential and elucidate the factors contributing to ligand binding in the protein's active site. The findings from MMPBSA/GBSA analysis indicated that these five selected small molecules closely approached the IC50 value of the reference ligand (OH8), yielding energy values of −34.85, −32.58, −31.71, and −30.39 kcal/mol, respectively. Additionally, an assessment of the interactions using hydrogen bond and dynamic analyses delineated the effective binding of the ligands with the binding pockets in the protein. Through computational analysis, we obtained valuable insights into the molecular mechanisms of GSK-3β, aiding in the development of more potent inhibitors.

Potencial terapêutico de fitoconstituintes de Pilocarpus microphyllus Stapf ex Wardlew. e da própolis na doença de Alzheimer: uma Revisão Integrativa

Introduction: Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by the deterioration of cognitive functions, for which the available pharmacotherapy is not capable of effecting a cure. Objectives: To investigate the neuroprotective properties of phytoconstituents from Jaborandi (Pilocarpus microphyllus) and propolis as potential agents in the therapy of AD. Methodology: This is an integrative literature review study, in which the PICO strategy was followed in formulating the guiding question. Five databases were used: PubMed, Web of Science, Scopus, Embase, and Lilacs. The analysis was conducted with the descriptors "epiisopiloturine", "episopilosin", "pilocarpine", "macaubine", "propolis", "alzheimer" extracted from the DeCS (Health Sciences Descriptors) and Medical Subject Headings (MeSH). Keywords were isolated and combined using boolean operators AND and OR. Results: The search resulted in 602 studies identified in the databases, 337 were duplicates, leaving 265 for title and abstract reading, of which 250 were excluded. In the end, 10 studies were read in full and 08 studies were included in the scope of the review. The research evidenced neuroprotective activity for propolis, through antioxidative, anti-inflammatory, and anticholinesterase action, configuring it with therapeutic potential in AD. For pilocarpine, a substance with various clinical applications, few studies demonstrated a correlation with AD, in cognitive and behavioral improvement. Conclusion: Therefore, benefits for the use of propolis in cognitive dysfunctions are concluded, while for pilocarpine, this relationship was not established. It is necessary to develop research that elucidates the possible functional roles for these substances.

Exosomes in Vascular/Neurological Disorders and the Road Ahead.

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.

Insights into amyloid precursor protein target through PPI network analysis.

Alzheimer's disease (AD) is the leading cause of dementia worldwide with therapeutic lacunae till date. The beta-amyloid (Aβ) accumulation triggers AD pathogenesis, though clinical trials lowering Aβ have not altered disease outcomes suggesting other interacting factors to be identified for drug design of AD. Therefore, it is of interest to identify potential hub proteins interlinked with disease-driving pathways using a network-based approach for AD therapeutic designing. Literature mining was done to identify proteins implicated in AD etiology. Protein-protein interactions (PPIs) were retrieved from the STRING database and merged into a single network using Cytoscape 3.10.1. The hub proteins involved in AD etiology were predicted based on the topological algorithms of CytoHubba. Six major proteins, with STRING database identifiers - APP, BACE1, PSEN1, MAPT, APOE4 and TREM2, were identified to be involved in AD pathogenesis. The merged network of PPIs of these proteins contained 51 nodes and 211 edges, as predicted by Analyzer module of Cytoscape. The Amyloid precursor protein (APP) emerged as the highest-scoring hub protein across multiple centrality measures and topological algorithms. Thus, current data provides evidence to support the ongoing investigation of APP's multifaceted functions and therapeutic potential for AD.

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

Revealing the binding mechanism of BACE1 inhibitors through molecular dynamics simulations

Alzheimer’s disease is a debilitating neurodegenerative disorder, and the Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) is a key therapeutic target in its treatment. This study employs molecular dynamics simulations and binding energy analysis to investigate the binding interactions between BACE1 and four selected small molecules: CNP520, D9W, NB641, and NB360. The binding model analysis indicates that the binding of BACE1 with four molecules are stable, except the loop regions show significant fluctuation. The binding free energy analyses reveal that NB360 exhibits the highest binding affinity with BACE1, surpassing other molecules (CNP520, D9W, and NB641). Detailed energy component assessments highlight the critical roles of electrostatic interactions and van der Waals forces in the binding process. Furthermore, residue contribution analysis identifies key amino acids influencing the binding process across all systems. Hydrogen bond analysis reveals a limited number of bonds between BACE1 and each small molecule, highlighting the importance of structural modifications to enable more stable hydrogen bonds. This research provides valuable insights into the molecular mechanisms of potential Alzheimer’s disease therapeutics, guiding the way for improved drug design and the development of effective treatments targeting BACE1. Communicated by Ramaswamy H. Sarma

Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease.

Rationale: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) δ is a potential target for AD. However, its regulatory mechanisms and therapeutic potential in AD remain unclear. We aimed to investigate if the activation of PPARδ using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a inhibited amyloid plaque deposition by suppressing the expression of neuronal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and reduced abnormal glial hyperactivation and inflammatory responses, resulting in improved learning and memory in the APP/PS1 mouse model of AD. Conclusion: We identified that specific activation of PPARδ provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPARδ as a promising drug target for treating AD.

A novel ferroptosis inhibitor, Thonningianin A, improves Alzheimer's disease by activating GPX4.

Background: Ferroptosis, a recently unveiled iron-dependent form of cellular demise, has emerged as a pivotal process contributing to the pathology of Alzheimer's Disease (AD). Glutathione Peroxidase 4 (GPX4), a vital defense mechanism countering ferroptosis by nullifying lipid peroxides and maintaining cellular redox equilibrium, has garnered significant attention in AD. Thus, identifying ferroptosis inhibitors to target GPX4 activation may help mitigate neuronal damage and impede AD progression. Objectives: We aimed to screen potent ferroptosis inhibitors and investigate their mechanism of action and therapeutic potential in AD, as well as lay the groundwork for future research in this promising area of study. Methods: This study employed a natural compound library to screen potential ferroptosis inhibitors in RAS-selective lethal compounds 3 (RSL-3)-induced PC-12 cells. Ferroptosis was evaluated by examining the mitochondrial morphology and function, reactive oxygen species (ROS) production, and lipid peroxide levels. The ability to chelate iron and intracellular iron levels was determined by UHPLC-Q/TOF-MS/MS and PGSK staining, respectively. APP Swe/ind- or Tau P301L-overexpressing PC-12 cells, and Amyloid-β transgenic CL4176 and Tau transgenic BR5270 Caenorhabditis elegans were employed as cellular and animal models of AD. Results: Thonningianin A (ThA) was identified as a novel ferroptosis inhibitor, as demonstrated by augmented cellular viability, mitigated mitochondrial impairment, diminished lipid peroxides, iron levels, and ROS generation. Mechanistically, ThA binds with GPX4 and enhances the AMPK/Nrf2 signaling pathway to stimulate GPX4 activation, effectively inhibiting ferroptosis. Moreover, in cellular and Caenorhabditis elegans AD models, ThA substantially inhibits ferroptosis by reducing ROS, lipid peroxide generation, and iron accumulation. Furthermore, ThA significantly delays paralysis, ameliorates food-sensing deficits and increases worms' antioxidative capacity. Conclusion: ThA ameliorates AD by inhibiting neuronal ferroptosis mediated by GPX4 activation through its binding with GPX4 and the upregulation of the AMPK/Nrf2/GPX4 pathway.

Baicalein promotes the microglia M2 polarization and suppresses apoptosis by targeting HMOX1/PDE4D to alleviate Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder that has quickly becoming one of the most expensive, lethal, and burdening diseases of this century. In the past twenty years, hundreds of drugs have been tested while only several have been authorized by FDA for AD treatment, hence, searching for candidate agent with therapeutic potential for AD is imminent. Controlling polarization direction of microglia is crucial in AD therapy. Recent research suggests that baicalein has potential to reduce neuroinflammation and prevent neurodegenerative diseases by affecting microglia, while the specific molecular mechanism of baicalein in regulating microglia in the treatment of AD is still unclear. In this study, we investigated how baicalein affected microglial polarization in AD and potential biological mechanisms. In cell experiments, it was verified that baicalein significantly shifted the BV-2 microglia phenotype from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, inhibited the microglial apoptosis and pro-inflammatory factors, promoted the microglial Aβ uptake and anti-inflammatory factors after LPS stimulated. In APP/PS1 mice, it was found that baicalein decreased the Aβ plaque deposition in brain, attenuated NLRP3 inflammasome activation and neuronal apoptosis in APP/PS1 mice. Furthermore, bioinformatics analysis and experiment validated that HMOX1 is a target of baicalein, and we elucidated that baicalein modulated the microglial polarization to inhibit neuroinflammation and neural injury through targeting on the HMOX1/PDE4D axis in AD. In conclusion, our findings indicate the therapeutic effect of baicalein for AD, and baicalein might serve a potential agent for AD treatment.

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.

Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes. To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing. We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound. This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.

Modulating the RAGE-Induced Inflammatory Response: Peptoids as RAGE Antagonists.

While the primary pathology of Alzheimer's disease (AD) is defined by brain deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end-products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD-associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood-brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V-domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide-induced pro-inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid-based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.

A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site.

A disintegrin and metalloproteinase (ADAM) family proteins are a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell surface protein ectodomains, including amyloid precursor protein (APP). Human ADAM 9, 10, and 17 proteolyze APPs and produce non-amyloid-genic p3 peptides, instead of neurotoxic amyloid-β peptides (Aβs; Aβ40 and Aβ42), which form fibrils and accumulate in the brain of patients with Alzheimer's disease (AD). The ADAM family is closely related to snake venom metalloproteinases (SVMPs), which are derived from ancestral ADAMs but act as soluble proteinases. To test the therapeutic potential of SVMPs, we purified SVMPs from Protobothrops flavoviridis venom using metal ion affinity and pooled into a cocktail. Thus, 9 out of 11 SVMPs in the P. flavoviridis genome were identified in the cocktail. SVMPs inhibited Aβ secretion when added to human cell culture medium without affecting APP proteolysis. SVMPs degraded synthetic Aβ40 and Aβ42 peptides at the same cleavage site (α-site of APP) as ADAM9, 10, and 17. SVMPs did not degrade Aβ fibrils but interfered with their formation, assessed using thioflavin-T. Thus, SVMPs have therapeutic potential for AD as an Aβ-degrading protease, and the finding adds to the discovery of bioactive peptides from venoms as novel therapeutics.

Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression.

Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.

Gut microbiota regulates blood‐cerebrospinal fluid barrier function and Aβ pathology

Accumulating evidence indicates that gut microbiota dysbiosis is associated with increased blood–brain barrier (BBB) permeability and contributes to Alzheimer's disease (AD) pathogenesis. In contrast, the influence of gut microbiota on the blood‐cerebrospinal fluid (CSF) barrier has not yet been studied. Here, we report that mice lacking gut microbiota display increased blood‐CSF barrier permeability associated with disorganized tight junctions (TJs), which can be rescued by recolonization with gut microbiota or supplementation with short‐chain fatty acids (SCFAs). Our data reveal that gut microbiota is important not only for the establishment but also for the maintenance of a tight barrier. Also, we report that the vagus nerve plays an important role in this process and that SCFAs can independently tighten the barrier. Administration of SCFAs in AppNL‐G‐F mice improved the subcellular localization of TJs at the blood‐CSF barrier, reduced the β‐amyloid (Aβ) burden, and affected microglial phenotype. Altogether, our results suggest that modulating the microbiota and administering SCFAs might have therapeutic potential in AD via blood‐CSF barrier tightening and maintaining microglial activity and Aβ clearance.

Ameliorative effect of Luffa cylindrica fruits on Caenorhabditis elegans and cellular models of Alzheimer's disease-related pathology via autophagy induction.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder without an effective cure. Natural products, while showing promise as potential therapeutics for AD, remain underexplored. This study was conducted with the goal of identifying potential anti-AD candidates from natural sources using Caenorhabditis elegans (C. elegans) AD-like models and exploring their mechanisms of action. Our laboratory's in-house herbal extract library was utilized to screen for potential anti-AD candidates using the C. elegans AD-like model CL4176. The neuroprotective effects of the candidates were evaluated in multiple C. elegans AD-like models, specifically targeting Aβ- and Tau-induced pathology. In vitro validation was conducted using PC-12 cells. To investigate the role of autophagy in mediating the anti-AD effects of the candidates, RNAi bacteria and autophagy inhibitors were employed. The ethanol extract of air-dried fruits of Luffa cylindrica (LCE), a medicine-food homology species, was found to inhibit Aβ- and Tau-induced pathology (paralysis, ROS production, neurotoxicity, and Aβ and pTau deposition) in C. elegans AD-like models. LCE was non-toxic and enhanced C. elegans' health. It was shown that LCE activates autophagy and its anti-AD efficacy is weakened with the RNAi knockdown of autophagy-related genes. Additionally, LCE induced mTOR-mediated autophagy, reduced the expression of AD-associated proteins, and decreased cell death in PC-12 cells, which was reversed by autophagy inhibitors (bafilomycin A1 and 3-methyladenine). LCE, identified from our natural product library, emerged as a valuable autophagy enhancer that effectively protects against neurodegeneration in multiple AD-like models. RNAi knockdown of autophagy-related genes and cotreatment with autophagy inhibitors weakened its anti-AD efficacy, implying a critical role of autophagy in mediating the neuroprotective effects of LCE. Our findings highlight the potential of LCE as a functional food or drug for targeting AD pathology and promoting human health.

Histaminergic neurotransmission in aging and Alzheimer's disease: A review of therapeutic opportunities and gaps.

Alzheimer's disease (AD) is a progressive neurodegenerative disorderfeaturing a brain accumulation of extracellular β-amyloidplaques (Aβ) and intracellular neurofibrillary tautangles (NFTs). Although cognitive decline is a disease-defining symptom of AD, sleep dysfunction, a common symptom often preceding cognitive decline, hasrecently gained more attention as a core AD symptom. Polysomnography and othersleep measures show sleep fragmentation with shortening of N3 sleep togetherwith excessive daytime sleepiness (EDS) and sundowning as the main findings in AD patients. The latter reflects dysfunction of the wake-promoting neurons (WPNs), including histaminergic neurons (HAN) located in thetuberomammillary nucleus (TMN) of the posterior hypothalamus, which projectunmyelinated axons to various parts of the brain. Histamine's role in cognitionand arousal is broadly recognized. Selective targeting of histaminergic subtype-3 and 4 receptors show therapeutic potential in rodent models of AD andaging. Based on PubMed, Scopus, and google scholar databases search, this review summarizes the current knowledge on the histaminergic system in AD and aging, its therapeutic potential in AD, and highlight areas where moreresearch is needed. Animal studies have demonstrated that pharmacological manipulation of histaminergic receptors or histamine supplementation improves cognition in AD models. However, measurements of HA or HA metabolite levels in the human brainand CSF present contradictory reports due to either lack of power or controls for known confounders. Systemic studies including broad age, sex, neuropathological diagnosis, and disease stage are warranted to fill the gap in our current understanding of the histaminergic neurotransmitter/neuromodulator system in humans, especially age-related changes, and therapeuticpotential of histamine in AD-related dysfunction.

Peptoids as potential therapeutics to reduce S100B-induced RAGE-associatedneuroinflammation in Alzheimer's disease.

Receptor for advanced glycation end-products (RAGE)-associated chronic neuroinflammation has been linked with Alzheimer's disease (AD) pathology. RAGE ligand S100B, which is elevated in AD brain, can induce release of inflammatory cytokines and upregulate RAGE. Consequently, targeting RAGE to reduce chronic inflammation represents a novel therapeutic strategy for AD. Peptoids are ideal potential AD therapeutics as they resist proteolytic degradation by repositioning side-chains from the α-carbon to the amide nitrogen and exhibit facile blood-brain barrier permeability. Peptoids designed to mimic RAGE ligands demonstrated strong binding affinity to RAGE in our previous studies. We hypothesize that these peptoids can attenuate S100B-induced activation of RAGE, thus reducing pro-inflammatory cytokine release associated with chronic neuroinflammation. Differentiated THP-1 macrophages were exposed to chronic low-levels of S100B to confirm upregulation of cytokine release. Macrophages were then treated with 0-50-μM peptoids (JPT1 or JPT1a) in the presence of S100B. To observe peptoid modulation of S100B-induced inflammation, cytokine analysis via immunoassay was performed using cell culture supernatants. Additionally, RAGE was incubated in the presence of 0-500-nM peptoid to achieve equilibrium. Unbound RAGE was quantified via modified ELISA to determine the binding affinity. S100B-treated THP-1 macrophages elicited anticipated inflammatory response evidenced by dose-dependent upregulation of cytokines. When THP-1 macrophages were incubated with peptoids and S100B, peptoids attenuated these S100B-induced inflammatory responses. Moreover, the peptoids demonstrated nanomolar binding affinity for RAGE. Peptoids modulate inflammatory responses induced by RAGE ligand S100B, including inflammatory cytokine release. These results implicate peptoids as a potential therapeutic agent for not only AD but also other inflammation-related illnesses. Because these peptoids have additionally exhibited the ability to modulate Aβ aggregation and transform the morphology of the aggregates formed, they may function as dual-target therapeutics for AD.