Potential For Treatment Of Alzheimer's Disease Research Articles

Identification of biomarkers and molecular mechanisms implicated in genetic variations underlying Alzheimer's disease pathogenesis

We analyzed data from human genome-wide association studies (GWASs) to identify genetic variants and biological pathways linked to Alzheimer's disease (AD). Ten AD biomarkers (APOE, NECTIN2, APOC1, APOC1P1, TOMM40, RNU4-67P, KRAS, Y_RNA, THORLNC, LINC01956) were found across studies, including six central genetic variants (MAPT (rs242557-A), GRIN2B (rs74442473-G), APOE (rs438811-T), ANK3 (rs438811-T), BIN1 (rs744373-G), and BDNF (rs7481773-A)). ANK3 (rs438811-T) and GRIN2B (rs74442473-G) were essential hub biomarkers for amyloid plaques, while MAPT (rs242557-A) and BIN1 (rs744373-G) were crucial for neurofibrillary tangles (NFTs). Higher-risk AD biomarkers were associated with increased protein-lipid complex formation, while lower-risk AD biomarkers were correlated with improved synaptic function. Six essential miRNAs (hsa-miR-124–3p, 15a-5p, 16–5p, 204–5p, 520g-3p, 520h) and three transcription factors (ZMAT4, ZBED6, FOXG1) emerged as possible candidates to reveal the genetic differences that lead to amyloid plaques, NFTs, and ultimately AD. These findings serve as a basis for potential AD treatments and offer new avenues for therapeutic approaches to directly target the genetic variations and processes associated with the disease.

Possible Prophylactic Effects of Sulforaphane on LPS-Induced Recognition Memory Impairment Mediated by Regulating Oxidative Stress and Neuroinflammatory Proteins in the Prefrontal Cortex Region of the Brain.

Alzheimer's disease (AD) presents a significant global health concern, characterized by neurodegeneration and cognitive decline. Neuroinflammation is a crucial factor in AD development and progression, yet effective pharmacotherapy remains elusive. Sulforaphane (SFN), derived from cruciferous vegetables and mainly from broccoli, has shown a promising effect via in vitro and in vivo studies as a potential treatment for AD. This study aims to investigate the possible prophylactic mechanisms of SFN against prefrontal cortex (PFC)-related recognition memory impairment induced by lipopolysaccharide (LPS) administration. Thirty-six Swiss (SWR/J) mice weighing 18-25 g were divided into three groups (n = 12 per group): a control group (vehicle), an LPS group (0.75 mg/kg of LPS), and an LPS + SFN group (25 mg/kg of SFN). The total duration of the study was 3 weeks, during which mice underwent treatments for the initial 2 weeks, with daily monitoring of body weight and temperature. Behavioral assessments via novel object recognition (NOR) and temporal order recognition (TOR) tasks were conducted in the final week of the study. Inflammatory markers (IL-6 and TNF), antioxidant enzymes (SOD, GSH, and CAT), and pro-oxidant (MDA) level, in addition to acetylcholine esterase (AChE) activity and active (caspase-3) and phosphorylated (AMPK) levels, were evaluated. Further, PFC neuronal degeneration, Aβ content, and microglial activation were also examined using H&E, Congo red staining, and Iba1 immunohistochemistry, respectively. SFN pretreatment significantly improved recognition memory performance during the NOR and TOR tests. Moreover, SFN was protected from neuroinflammation and oxidative stress as well as neurodegeneration, Aβ accumulation, and microglial hyperactivity. The obtained results suggested that SFN has a potential protective property to mitigate the behavioral and biochemical impairments induced by chronic LPS administration and suggested to be via an AMPK/caspase-3-dependent manner.

Effectiveness of Personalized Hippocampal Network–Targeted Stimulation in Alzheimer Disease

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. ClinicalTrials.gov Identifier: NCT04260724.

Discovery of a novel chemotype as DYRK1A inhibitors against Alzheimer's disease: Computational modeling and biological evaluation

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) plays an essential role in Tau and Aβ pathology closely related to Alzheimer's disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitor for clinical use as anti-AD therapy. This is somewhat due to the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and two amino acid residues named GLU239 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect the SH-SY5Y human neuroblastoma cell line from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction of 3 × Tg-AD mice, ameliorated pathological changes, and attenuated Tau hyperphosphorylation as well as Aβ deposition. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study.

PRG ameliorates cognitive impairment in Alzheimer's disease mice by regulating β-amyloid and targeting the ERK pathway

BackgroundPRG is derived from Phellinus ribis and is a homogeneous polysaccharide with well-defined structural information. PRG was found to have significant in vitro neurotrophic and neuroprotective activities. Thus, PRG might be a potential treatment for Alzheimer's disease. However, the related mechanisms of action are still unclear, so deeper in vivo experimental validation and the potential mechanisms need to be investigated. PurposeThe effects of PRG on AD mice were investigated using Senescence-accelerated SAMP8 mice as an AD model to elucidate the crucial molecular mechanisms. MethodsPRG was obtained from Phellinus ribis by water-alcohol precipitation, column chromatography, and ultrafiltration. The Morris water maze and novel object recognition behavioral assays were used to evaluate the effects of PRG in AD mice. Nissl staining, the TUNEL apoptosis assay, and Golgi staining were used to assess brain neuronal cell damage, apoptosis, and neuronal status. Enzyme-linked immunosorbent assays, Western blotting, and immunofluorescence were used to explore the impacts of correlated factors and protein pathways under relevant mechanisms. ResultsThe findings suggest that PRG improved learning ability and spatial memory capacity in SAMP8 mice. PRG hastened the disintegration of β-amyloid, reduced the content and abnormal accumulation of the toxic Aβ1-42 protein, and decreased apoptosis. PRG activated the BDNF/ERK/CREB signaling pathway through a cascade, exerted neurotrophic effects, regulated cell proliferation and differentiation, increased neuronal dendritic branching and spine density, and improved synaptic plasticity. ConclusionPRG promoted β-amyloid degradation to reduce neuronal damage and apoptosis. It exerted neurotrophic effects by activating the BDNF/ERK/CREB pathway, promoting neuronal dendritic branching and dendritic spine growth, regulating cell proliferation and differentiation, and improving synaptic plasticity, which improved AD. Taken together, as a novel natural active polysaccharide with a well-defined structure, PRG affected AD symptoms in senescence-accelerated mice by interacting with multiple targets. The results indicate that PRG is a promising potential anti-AD drug candidate.

BACE1 Inhibition Utilizing Organic Compounds Holds Promise as a Potential Treatment for Alzheimer's and Parkinson's Diseases.

Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1). In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates. This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations. Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable. The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors.

Antioxidant Efficacy of Hwangryunhaedok-tang through Nrf2 and AMPK Signaling Pathway against Neurological Disorders In Vivo and In Vitro.

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aβ), and Aβ-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09®), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aβ, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.

7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer's disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer's disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid β40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.

Competitive Inhibition and Synergistic Effects of Nutraceutical and Metabolite Molecules on Anti-Acetylcholinesterase Activity

The rapidly increasing prevalence of Alzheimer's disease (AD) poses a significant global public health threat. While medications such as Donepezil, Galantamine, and Rivastigmine are used, their serious side effects and limited healing fail to provide a definite cure. Consequently, combination therapies are being explored to enhance the efficacy of existing drugs. This study aims to evaluate the anti-acetylcholinesterase activities of previously identified nutraceutical and metabolite compounds, namely Queuine, Etoperidone, and Thiamine. Combined use of Queuine with Donepezil, Etoperidone, and Thiamine on acetylcholinesterase enzyme inhibition is also evaluated. The effects of the drug combinations on cell viability and acetylcholinesterase inhibition were investigated by using safe doses determined for each drug. The cytotoxic effect of drug combinations was investigated on the SH-SY5Y cell line using the RTCA method. All the individual or drug combinations were non-toxic to neuronal cells. Anti-acetylcholinesterase activities were estimated by Ellman’s method yielding the inhibition percentages as 70%, 61%, 45%, and 51% for Donepezil, Etoperidone, Queuine, and Thiamine, respectively. When drug combinations were analyzed, competitive inhibition resulted for Queuine+Donepezil and Queuine+Thiamine, the enzyme inhibition percentages being diminished to 47% and 21%, respectively. A significant synergistic effect was observed for Queuine+Etoperidone with the highest inhibition of 74%. This study provides the first evidence of the nutraceutical molecule Queuine's impact on acetylcholinesterase inhibition and the synergistic effect of Queuine and Etoperidone as a potent drug combination surpassing the effectiveness of Donepezil. Queuine and Etoperidone synergism may serve as a potential AD treatment by further in vivo validations.

Borneol-Modified Schisandrin B Micelles Cross the Blood-Brain Barrier To Treat Alzheimer's Disease in Aged Mice.

Objective: Schisandrin B (Sch B) is a bioactive dibenzocyclooctadiene derizative that is prevalent in the fruit of Schisandra chinensis. Numerous studies have demonstrated that Sch B has a neuroprotective action by reducing oxidative stress and effectively preventing inflammation. It follows that Sch B is a potential treatment for Alzheimer's disease (AD). However, the drug's solubility, bioavailability, and lower permeability of the blood-brain barrier (BBB) can all reduce its efficacy during the therapy process. Therefore, this study constructed borneol-modified schisandrin B micelles (Bor-Sch B-Ms), which increase brain targeting by accurately delivering medications to the brain, effectively improving bioavailability. High therapeutic efficacy has been achieved at the pathological site. Methods: Bor-Sch B-Ms were prepared using the thin film dispersion approach in this article. On the one hand, to observe the targeting effect of borneol, we constructed a blood-brain barrier (BBB) model in vitro and studied the ability of micelles to cross the BBB. On the other hand, the distribution of micelle drugs and their related pharmacological effects on neuroinflammation, oxidative stress, and neuronal damage were studied through in vivo administration in mice. Results: In vitro studies have demonstrated that the drug uptake of bEnd.3 cells was increased by the borneol alteration on the surface of the nano micelles, implying that Bor-Sch B-Ms can promote the therapeutic effect of N2a cells. This could result in more medicines entering the BBB. In addition, in vivo studies revealed that the distribution and circulation time of medications in the brain tissue were significantly higher than those in other groups, making it more suitable for the treatment of central nervous system diseases. Conclusion: As a novel nanodrug delivery system, borneol modified schisandrin B micelles have promising research prospects in the treatment of Alzheimer's disease.

Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited the inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.

Tip-enhanced Raman spectroscopy reveals the structural rearrangements of tau protein aggregates at the growth phase.

Tau protein aggregates inside neurons in the course of Alzheimer's disease (AD). Because of the enormous number of people suffering from AD, this disease has become one of the world's major health and social problems. The presence of tau lesions clearly correlates with cognitive impairments in AD patients, thus, tau is the target of potential treatments for AD, next to amyloid-β. The exact mechanism of tau aggregation has not been understood in detail so far; especially little is known about the structural rearrangements of tau aggregates at the growth phase. The research into tau conformation at each step of the aggregation pathway will contribute to the design of effective therapeutic approaches. To follow the secondary structure of individual tau aggregates at the growth phase, we applied tip-enhanced Raman spectroscopy (TERS). The nanospectroscopic approach enabled us to follow the structure of individual aggregates occurring in the subsequent phases of tau aggregation. We applied multivariate data analysis to extract the spectral differences for tau aggregates at different aggregation phases. Moreover, atomic force microscopy (AFM) allowed the tracking of the morphological alterations for species occurring with the progression of tau aggregation.

Hyperbaric oxygen alleviates selective domains of cognitive and motor deficits in female 5xFAD mice.

Treatment of Alzheimer's disease (AD) has been limited to managing of symptoms or anti-amyloid therapy with limited results and uncertainty. Seeking out new therapies that can reverse the effects of this devastating disease is important. Hyperbaric oxygen (HBO) therapy could be such a candidate as it has been shown to improve brain function in certain neurological conditions. Furthermore, the role sex plays in the vulnerability/resilience to AD remains equivocal. An understanding of what makes one sex more vulnerable to AD could unveil new pathways for therapy development. In this study, we investigated the effects of HBO on cognitive, motor, and affective function in a mouse model of AD (5xFAD) and assessed protein oxidation in peripheral tissues as a safety indicator. The motor and cognitive abilities of 5xFAD mice were significantly impaired. HBO therapy improved cognitive flexibility and associative learning of 5xFAD females but not males, but HBO had no effect other aspects of cognition. HBO also reversed AD-related declines in balance but had no impact on gait and anxiety-like behavior. HBO did not affect body weights or oxidative stress in peripheral tissues. Our study provides further support for HBO therapy as a potential treatment for AD and emphasizes the importance of considering sex as a biological variable in therapeutic development. Further investigations into the underlying mechanisms of HBO's sex-specific responses are warranted, as well as optimizing treatment protocols for maximum benefits.

Biochemical characterization of chamomile essential oil: Antioxidant, antibacterial, anticancer and neuroprotective activity and potential treatment for Alzheimer's disease

Alzheimer’s disease (AD) causes dementia among older adults, increasing the global burden of dementia. Therefore, this study investigates the potential neuroprotective, antioxidant, and anticancer effects of chamomile essential oil (CCO) in Alzheimer’s disease. CCO’s main volatile compounds (VOCs) were α-bisabolol, camazulene, and bisabolol oxide A, representing 81 % of all VOCs. CCO scavenged 93 % of DPPH free radicals and inhibited the pathogenic bacteria, i.e., Staphylococcus aureus and Salmonella typhi, besides reducing 89 % of brain cancer cell lines (U87). Eighty albino rats were randomized into four groups: standard control, Alzheimer’s disease group caused by AlCl3, and treated groups. The results indicated that the mean value of tumor necrosis factor α (TNF-α), amyloid precursor protein (APP), amyloid beta (Aβ), caspase-3, & B-cell lymphoma 2 (Bcl-2) was significantly elevated due to the harmful effect of AlCl3; however, CCO downregulated these values, and this effect was attributed to the considerable volatile compounds and phenolic compounds content. Additionally, CCO rats showed a significant increment in noradrenergic (NE), dopaminergic (DO), and serotoninergic systems with relative increases of 50, 50, and 14 % compared to diseased rats. The brain histology of CCO-treated rats showed a significant reduction in neuronal degeneration and improved brain changes, and its histology was close to that of the control brain. The results indicated that CCO offers a new strategy that could be used as an antioxidant and neuroprotective agent for AD due to its considerable contents of antioxidants and anti-inflammatory compounds.

Luteolin: Nature's promising warrior against Alzheimer's and Parkinson's disease.

Neurodegenerative disorders (NDs) are defined as the slow loss of a group of neurons that are particularly sensitive. Due to the intricate pathophysiological processes underlying neurodegeneration, no cure exists for these conditions despite the extensive research and advances in our knowledge of the onset and course of NDs. Hence, there is a medical need for the creation of a novel therapeutic approach for NDs. By focusing on numerous signaling pathways, some natural substances derived from medicinal herbs and foods have demonstrated potent activity in treating various NDs. In this context, flavonoids have recently attracted increased popularity and research attention because of their alleged beneficial effects on health. By acting as antioxidant substances, nutritional supplements made up of flavonoids have been found to lessen the extent of NDs like Alzheimer's disease (AD) and Parkinson's disease (PD). Luteolin is a flavone that possesses potent antioxidant and anti-inflammatory properties. As a consequence, luteolin has emerged as an option for treatment with therapeutic effects on many brain disorders. More research has focused on luteolin's diverse biological targets as well as diverse signaling pathways, implying its potential medicinal properties in several NDs. This review emphasizes the possible use of luteolin as a drug of choice for the treatment as well as the management of AD and PD. In addition, this review recommends that further research should be carried out on luteolin as a potential treatment for AD and PD alongside a focus on mechanisms and clinical studies.

Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer's disease

A series of novel hybrid compounds were designed, synthesized, and utilized as multi-target drugs to treat Alzheimer's disease (AD) by connecting capsaicin and tacrine moieties. The biological assays indicated that most of these compounds demonstrated strong inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities with IC50 values in the nanomolar, as well as good blood–brain barrier permeability. Among the synthesized hybrids, compound 5s displayed the most balanced inhibitory effect on hAChE (IC50 = 69.8 nM) and hBuChE (IC50 = 68.0 nM), and exhibited promising inhibitory activity against β-secretase-1 (BACE-1) (IC50 = 3.6 µM). Combining inhibition kinetics and molecular model analysis, compound 5s was shown to be a mixed inhibitor affecting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. Additionally, compound 5s showed low toxicity in PC12 and BV2 cell assays. Moreover, compound 5s demonstrated good tolerance at the dose of up to 2500 mg/kg and exhibited no hepatotoxicity at the dose of 3 mg/kg in mice, and it could effectively improve memory ability in mice. Taken together, these findings suggest that compound 5s is a promising and effective multi-target agent for the potential treatment of AD.

Memantine protects the cultured rat hippocampal neurons treated by NMDA and amyloid β1-42.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with no effective treatments. Recent research highlights the role of NMDA receptors in AD development, as excessive activation of these receptors triggers excitotoxicity. Memantine, an NMDA receptor antagonist, shows promise in curbing excitotoxicity. What sets our study apart is our novel exploration of memantine's potential to protect hippocampal neurons from neurotoxicity induced by NMDA and amyloid β1-42, a hallmark of AD. To achieve this, we conducted a series of experiments using rat hippocampal cell cultures. We employed Hoechst and propidium iodide double staining to assess neuronal viability. Analyzing the viability of neurons in normal conditions compared to their status after 24 h of exposure to the respective agents revealed compelling results. The incubation of hippocampal neurons with NMDA or amyloid β1-42 led to a more than twofold increase in the number of apoptotic and necrotic neurons. However, when memantine was co-administered with NMDA or amyloid β1-42, we witnessed a notable augmentation in the number of viable cells. This unique approach not only suggests that memantine may act as a neuroprotective agent but also emphasizes the relevance of hippocampal neuron cultures as valuable models for investigating excitotoxicity and potential AD treatments.

Ferroptotic Potency of ISM1 Expression in the Drug-Induced Alzheimer's Disease-Like Phenotype Under the Influence of Betulin.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by two main pathological mechanisms, mostly hyperphosphorylated tau and amyloid-β toxicity. Although many studies focus on these basic mechanisms, ferroptosis draws attention as an important pathway responsible for neurodegeneration in AD. There is no definitive treatment for AD but alternative phytochemicals to drugs come into prominence. Betulin is usually obtained from the birch tree. It is an abundant triterpene and has a high antioxidant capacity. Isthmin-1 (ISM1) is a secreted adipokine. In this study, we investigated the potential treatment of AD in the ferroptosis-ISM1-betulin triangle. For this, we created an AD model with okadaic acid (200 ng/kg)) in 36 Wistar albino male rats and treated with betulin (20 mg/kg/day, i.p). We evaluated ISM1 gene expression, iron accumulation, and total oxidative metabolism parameters (TAS, TOS, OSI) in hippocampal tissue. We analyzed cognitive recovery in AD with Morris Water Maze Test and general locomotor activity, explore, and anti-anxiolytic effect with Open Field Test. We compared the obtained data with metabolic and genetic results. In conclusion, betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Betulin may have a role in neuronal ferroptotic mechanisms by reducing iron accumulation by ISM1 regulation. Although this study suggests the corrective effect of betulin and ISM1 on cognitive gain and anxiety, it is the first study to show the total antioxidant capacity of betulin in AD.

Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by Integrating Virtual Screening and In Vitro Validation.

Uncaria rhynchophylla (Gouteng in Chinese, GT) is the main medicine in many traditional recipes in China. It is commonly used to alleviate central nervous system (CNS) disorders, although its mechanism in Alzheimer's disease is still unknown. This study was designed to predict and validate the underlying mechanism in AD treatment, thus illustrating the biological mechanisms of GT in treating AD. In this study, a PPI network was constructed, KEGG analysis and GO analysis were performed, and an "active ingredient-target-pathway" network for the treatment of Alzheimer's disease was constructed. The active ingredients of GT were screened out, and the key targets were performed by molecular docking. UHPLC-Q-Exactive Orbitrap MS was used to screen the main active ingredients and was compared with the network pharmacology results, which verified that GT did contain the above ingredients. A total of targets were found to be significantly bound up with tau, Aβ, or Aβ and tau through the network pharmacology study. Three SH-SY5Y cell models induced by okadaic acid (OA), Na2S2O4, and H2O2 were established for in vitro validation. We first found that GT can reverse the increase in the hyperphosphorylation of tau induced by OA to some extent, protecting against ROS damage. Moreover, the results also indicated that GT has significant neuroprotective effects. This study provides a basis for studying the potential mechanisms of GT in the treatment of AD.

Discovery of novel multifunctional ligands targeting GABA transporters, butyrylcholinesterase, β-secretase, and amyloid β aggregation as potential treatment of Alzheimer's disease

Alzheimer's disease (AD) is a global health problem in the medical sector that will increase over time. The limited treatment of AD leads to the search for a new clinical candidate. Considering the multifactorial nature of AD, a strategy targeting number of regulatory proteins involved in the development of the disease is an effective approach. Here, we present a discovery of new multi-target-directed ligands (MTDLs), purposely designed as GABA transporter (GAT) inhibitors, that successfully provide the inhibitory activity against butyrylcholinesterase (BuChE), β-secretase (BACE1), amyloid β aggregation and calcium channel blockade activity. The selected GAT inhibitors, 19c and 22a – N-benzylamide derivatives of 4-aminobutyric acid, displayed the most prominent multifunctional profile. Compound 19c (mGAT1 IC50 = 10 μM, mGAT4 IC50 = 12 μM and BuChE IC50 = 559 nM) possessed the highest hBACE1 and Aβ40 aggregation inhibitory activity (IC50 = 1.57 μM and 99 % at 10 μM, respectively). Additionally, it showed a decrease in both the elongation and nucleation constants of the amyloid aggregation process. In contrast compound 22a represented the highest activity and a mixed-type of eqBuChE inhibition (IC50 = 173 nM) with hBACE1 (IC50 = 9.42 μM), Aβ aggregation (79 % at 10 μM) and mGATs (mGAT1 IC50 = 30 μM, mGAT4 IC50 = 25 μM) inhibitory activity. Performed molecular docking studies described the mode of interactions with GATs and enzymatic targets. In ADMET in vitro studies both compounds showed acceptable metabolic stability and low neurotoxicity. Successfully, compounds 19c and 22a at the dose of 30 mg/kg possessed statistically significant antiamnesic properties in a mouse model of amnesia caused by scopolamine and assessed in the novel object recognition (NOR) task or the passive avoidance (PA) task.