Treatment Of Alzheimer's Disease Research Articles

EFFICACY OF CANNABIDIOL (CBD) IN THE TREATMENT OF ALZHEIMER'S DISEASE: A CRITICAL REVIEW OF EVIDENCE AND CLINICAL IMPLICATIONS

Introduction: This study investigates the therapeutic potential of cannabidiol (CBD) in treating Alzheimer's disease (AD), which is characterized by progressive cognitive decline, memory impairment, and behavioral changes. As traditional treatment options are limited, the exploration of alternative therapies, including CBD, has gained prominence in recent years. Objective: The aim of this research is to evaluate the efficacy of CBD in modulating neuroinflammation and oxidative stress, as well as its potential impact on slowing the progression of Alzheimer's disease. Method: A literature review was conducted using ten articles published between 2019 and 2024. Databases such as the Virtual Health Library, LILACS Plus, and Medline were utilized, applying descriptors related to CBD and Alzheimer's disease. The articles were filtered based on specific inclusion criteria, focusing on studies published in Portuguese, Spanish, and English that are freely accessible online. Results: The reviewed literature indicates that CBD may inhibit the formation of beta-amyloid plaques, a hallmark of Alzheimer's pathology, suggesting its potential for both symptom relief and slowing disease progression. Additionally, the interaction between CBD and the endocannabinoid system (ECS) highlights its role in managing cognitive decline and memory issues associated with AD. Conclusion: While the findings are promising, there is a pressing need for more rigorous clinical studies to validate the efficacy and safety of CBD in Alzheimer's treatment. This research underscores the potential of cannabinoids as a therapeutic option in managing neurodegenerative diseases.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored. We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL-G-F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background. Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL-G-F/wt). Insoluble Aβ1-40 and Aβ1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL-G-F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1. Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

Acupuncture for patients with Alzheimer's disease: An evidence map of randomized controlled trials, systematic reviews, and meta-analysis.

Background: Acupuncture is an effective complementary treatment for Alzheimer's disease (AD). This review aims to summarize the available evidence provided by randomized controlled trials (RCTs) and systematic reviews (SRs) or meta-analyses (MAs) on the effect of acupuncture on AD. Objective: To systematically summarize and combine clinical research evidence on AD distribution. Methods: We conducted a comprehensive search of various databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Data, Chinese BioMedical Literature Database (CBM) and Chonqing VIP (CQVIP), from their inception to September 2023. Relevant literature about acupuncture for AD was included, and the characteristics of the evidence map were presented through charts and textual analyses. Results: In total, 117 RCTs and 17 SRs or MAs were included. The results were divided into three categories: basic characteristics of the included literature, clinical characteristics and quality assessment of the included RCTs, and clinical characteristics and quality assessment of the included SRs and MAs. Conclusions: Acupuncture as a therapeutic measure for AD has some advantages in improving cognition and quality of life; thus, it is imperative to conduct multi-center, large-scale RCTs to enhance the evidence supporting the use of acupuncture in AD. This is the first evidence map exploring acupuncture treatment for AD, providing insights into the current clinical research landscape on acupuncture treatment for AD. Furthermore, the findings of this study highlight research gaps in this field and serve as a valuable reference for guiding the planning and selection of topics for future research.

Novel role of curcumin as inhibitor of β-amyloid-induced lamin fragmentation.

Oligomer amyloid beta 42 (Aβ) is considered the key pathogenic molecule in Alzheimer disease (AD) and causes specific lamin fragmentation. Curcumin has been recognized for its protective effects against Aβ-induced toxicity in AD, though its underlying mechanism remains unclear. In this study, the inhibitory mechanism of curcumin against Aβ-induced lamin fragmentation and cell death was investigated. Human neuroblastoma cells were used to examine Aβ-induced lamin fragmentation and lamin deformation by immunoblotting and confocal microscopy, while cell viability was measured using MTT and alamarBlue assay. Caspase and cathepsin L activity were assessed by spectrofluorometry, and Aβ aggregation was evaluated by ThT assay. Our results demonstrated that curcumin inhibited Aβ aggregation, reducing intracellular Aβ uptake by 45% compared to Aβ-treated cells. Curcumin also inhibited the Aβ-induced intracellular calcium rise, subsequently leading to a onefold reduction in cathepsin L activity. This reduction in cathepsin L activity by curcumin blocked the Aβ-induced lamin fragmentation. Collectively, these findings suggest that curcumin inhibits Aβ-induced cell death by preventing Aβ entry and lamin cleavage, providing potential new insights for AD treatment.

Gaps in biomedical research in frontotemporal dementia: A call for diversity and disparities focused research.

Frontotemporal dementia (FTD) is one of the leading causes of young-onset dementia before age 65, typically manifesting as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). Although FTD affects all populations across the globe, knowledge regarding the pathophysiology and genetics derives primarily from studies conducted in North America and Western Europe. Globally, biomedical research for FTD is hindered by variable access to diagnosis, discussed in this group's earlier article, and by reduced access to expertise, funding, and infrastructure. This perspective paper was produced by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) and discusses the field's current status on the cross-cultural aspects of basic and translational research in FTD (including that focused on epidemiology, genetics, biomarkers, and treatment). It subsequently provides a summary of gaps and needs to address the disparities and advance global FTD biomedical research.

Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning

ABSTRACT BACE1 has been regarded as an essential drug design target for treating Alzheimer’s disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and molecular mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the molecular mechanism underlying the effect of D93 and D289 protonation on binding of inhibitors OV6 and 4B2 to BACE1. The GaMD trajectory-based DL successfully identifies significant function domains. Dynamic analysis shows that the protonation of D93 and D289 strongly affects the structural flexibility and dynamic behaviour of BACE1. Free energy landscapes indicate that inhibitor-bound BACE1s have more conformational states in the protonated states than the wild-type (WT) BACE1, and show more binding poses of inhibitors. Binding affinities calculated using the MM-GBSA method indicate that the protonation of D93 and D289 highly disturbs the binding ability of inhibitors to BACE1. In addition, the protonation of two residues significantly affects the hydrogen bonding interactions (HBIs) of OV6 and 4B2 with BACE1, altering their binding activity to BACE1. The binding hot spots of BACE1 recognized by residue-based free energy estimations provide rational targeting sites for drug design towards BACE1. This study is anticipated to provide theoretical aids for drug development towards treatment of AD.

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer’s disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers’ modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.

Acetylcholinesterase – glucose-regulated protein 78 binding site prediction, a hope to cure neurological disorders such as Alzheimer’s disease

Cerebral amyloid plaques in the brain define the elderly neuralgic disorder, Alzheimer’s disease (AD). The enzyme Acetylcholinesterase (AChE) was reported to play a vital role in AD. It was shown that AChE induces amyloid fibril formation forming highly toxic AChE-Amyloid-β (Aβ) complexes. AChE can accelerate amyloid formation, and its inhibition could prevent such alterations to the enzyme. Understanding the proteostasis of AChE and its binding site to cellular chaperone GRP78 (Glucose-regulated protein 78) would help find a treatment for AD. In this study, the state of the art computational tools were utilized to predict the binding location of AChE that can stably associate with the cellular chaperone, GRP78. Sequence comparison along with molecular docking predicts two binding locations on AChE (C69–C96 and C257–C272) that could bind to GRP78 substrate binding domain β (SBDβ). The analysis of the docking data suggests that the former location has the best average binding affinity value (-12.16 kcal/mol) and average interaction pattern (13.9 ± 3.5 H-bonds, 5.5 ± 1.4 hydrophobic contacts, and 1.4 ± 1.2 salt bridges).

40 Hz light preserves synaptic plasticity and mitochondrial function in Alzheimer’s disease model

Alzheimer’s disease (AD) is the most prevalent type of dementia. Its causes are not fully understood, but it is now known that factors like mitochondrial dysfunction, oxidative stress, and compromised ion channels contribute to its onset and progression. Flickering light therapy has shown promise in AD treatment, though its mechanisms remain unclear. In this study, we used a rat model of streptozotocin (STZ)-induced AD to evaluate the effects of 40 Hz flickering light therapy. Rats received intracerebroventricular (ICV) STZ injections, and 7 days after, they were exposed to 40 Hz flickering light for 15 min daily over seven days. Cognitive and memory functions were assessed using Morris water maze, novel object recognition, and passive avoidance tests. STZ-induced AD rats exhibited cognitive decline, elevated reactive oxygen species, amyloid beta accumulation, decreased serotonin and dopamine levels, and impaired mitochondrial function. However, light therapy prevented these effects, preserving cognitive function and synaptic plasticity. Additionally, flickering light restored mitochondrial metabolites and normalized ATP-insensitive mitochondrial calcium-sensitive potassium (mitoBKCa) channel activity, which was otherwise downregulated in AD rats. Our findings suggest that 40 Hz flickering light therapy could be a promising treatment for neurodegenerative disorders like AD by preserving synaptic and mitochondrial function.

Amyloid-beta antibody treatment in Alzheimer's disease : An update on recent data and outlook on implementation in clinical routine.

Amyloid-beta (Aβ) antibody treatment has emerged as apromising approach for the treatment of Alzheimer's disease (AD), targeting the accumulation of Aβ plaques, which are ahallmark of the disease. This review provides an update on recent clinical trial data, highlighting the efficacy and safety of various antibodies targeting Aβ. Recent trials have demonstrated that certain Aβ antibodies can reduce amyloid plaques and slow cognitive decline in patients with early AD. Key findings from trials of drugs are discussed, including their mechanisms of action, dosing regimens, and observed side effects. The potential for Aβ antibody therapy to be integrated into routine clinical practice is also explored. While Aβ antibody therapy represents asignificant advancement in AD treatment, ongoing research is needed to optimize their use and understand their long-term impact. This review underscores the importance of personalized medicine in AD and the need for continued innovation in therapeutic strategies.

Unveiling tomorrow: Carbonic anhydrase activators and inhibitors pioneering new frontiers in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H2O2 generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

Therapeutic Potential of Ramalin Derivatives with Enhanced Stability in the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) remains a significant public health challenge with limited effective treatment options. Ramalin, a compound derived from Antarctic lichens, has shown potential in the treatment of AD because of its strong antioxidant and anti-inflammatory properties. However, its instability and toxicity have hindered the development of Ramalin as a viable therapeutic agent. The primary objective of this study was to synthesize and evaluate novel Ramalin derivatives with enhanced stabilities and reduced toxic profiles, with the aim of retaining or improving their therapeutic potential against AD. The antioxidant, anti-inflammatory, anti-BACE-1, and anti-tau activities of four synthesized Ramalin derivatives (i.e., RA-Hyd-Me, RA-Hyd-Me-Tol, RA-Sali, and RA-Benzo) were evaluated. These derivatives demonstrated significantly improved stabilities compared to the parent compound, with RA-Sali giving the most promising results. More specifically, RA-Sali exhibited a potent BACE-1 inhibitory activity and effectively reduced tau phosphorylation, a critical factor in AD pathology. Despite exhibiting reduced antioxidant activities compared to the parent compound, these derivatives represent a potential multi-targeted approach for AD treatment, marking a significant step forward in the development of stable and effective AD therapeutics.

Altered immune response is associated with sex difference in vulnerability to Alzheimer's disease in human prefrontal cortex.

Alzheimer's disease (AD) is a neurodegenerative disorder with a higher risk incidence in females than in males, and there are also differences in AD pathophysiology between sexes. The role of sex in the pathogenesis of AD may be crucial, yet the cellular and molecular basis remains unclear. Here, we performed a comprehensive analysis using four public transcriptome datasets of AD patients and age-matched control individuals in prefrontal cortex, including bulk transcriptome (295 females and 402 males) and single-nucleus RNA sequencing (snRNA-seq) data (224 females and 219 males). We found that the transcriptomic profile in female control was similar to those in AD. To characterize the key features associated with both the pathogenesis of AD and sex difference, we identified a co-expressed gene module that positively correlated with AD, sex, and aging, and was also enriched with immune-associated pathways. Using snRNA-seq datasets, we found that microglia (MG), a resident immune cell in the brain, demonstrated substantial differences in several aspects between sexes, such as an elevated proportion of activated MG, altered transcriptomic profile and cell-cell interaction between MG and other brain cell types in female control. Additionally, genes upregulated in female MG, such as TLR2, MERTK, SPP1, SLA, ACSL1, and FKBP5, had high confidence to be identified as biomarkers to distinguish AD status, and these genes also interacted with some approved drugs for treatment of AD. These findings underscore the altered immune response in female is associated with sex difference in susceptibility to AD, and the necessity of considering sex factors when developing AD biomarkers and therapeutic strategies, providing a scientific basis for further in-depth studies on sex differences in AD.

Inhibition of Aβ Aggregation and Tau Phosphorylation with Functionalized Biomimetic Nanoparticles for Synergic Alzheimer's Disease Therapy.

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because of the poor brain bioavailability of drugs, which is attributed to the blood-brain barrier (BBB) restriction and complicated brain conditions. Herein, HM-DK was proposed for synergistic therapy of AD by using hollow mesoporous manganese dioxide (HM) as a carrier to deliver an Aβ-inhibiting peptide and a Dp-peptide inhibitor of Tau-related fibril formation synergistically. Inspired by 4T1 cancer cells promoting BBB penetration during brain metastasis, a prospective biomimetic nanocarrier (HM-DK@CM) encapsulated by 4T1 cell membranes was designed. After crossing the BBB, HM-DK@CM inhibited Aβ aggregation and prevented Tau phosphorylation simultaneously. Moreover, by taking advantage of the catalase-like activity of HM, HM-DK@CM relieved oxidative stress and altered the microenvironment associated with the development of AD. Compared with the single therapeutic drug, HM-DK@CM restored nerve damage and improved AD mice's learning and memory abilities by decreasing Aβ oligomer, p-Tau protein, and inflammation through various pathways for synergistic therapy, which has broad prospects for the effective treatment of AD.

Insight from molecular modeling and ADMET analysis: Design, synthesis and in vitro acetylcholinesterase and butyrylcholinesterase assessment of thiazolidinone containing benzoxazole hybrids derivatives

Alzheimer's disease (AD) is a brain disorder medically defined as loss of memory and analytical reasoning abilities of an infected person. The adult or aged peoples are more likely to be adversely affected by this disease. Following this prospect, this study is conducted to synthesize a novel class of (Z)-2-(((Z)-2-(benzo[d]oxazol-2-ylthio)-1-phenylethylidene)hydrazono)-3-phenylthiazolidin-4-one based derivatives and evaluate its performance towards the treatment of AD. This study showed the better results when compared to the inhibition potential of the standard drug Donepezil against AChE (IC50= 4.10 ± 1.05 µM) and against BuChE (IC50=6.59 ± 1.63 µM), the inhibition potential shown by benzimidazole based thiadiazole scaffolds against the targeted enzymes is of wide range. The inhibition potential of all the scaffolds against AChE ranged from 2.89 ± 0.65 µM to 19.04 ± 0.49 µM and against BuChE ranged from 3.70 ± 0.98 µM to 23.19 ± 0.71 µM. Moreover, to investigate the binding interaction of effective scaffolds against the active sites of AChE and BuChE, molecular docking studies were carried out and the analysis data evaluated the substantial binding interaction of scaffolds against the targeted enzymes. The structural characteristic of each scaffold is determined by using different spectroscopic techniques. In this work only three analogues found to be the most active having the observed IC50 values 7d, 3.05 ± 0.19 µM, 2.90 ± 0.87 µM(for BuChE), 7g, 3.88 ± 0.32 µM(for AChE), 4.98 ± 0.54 µM(for BuChE), 7k 2.89 ± 0.65 µM(for AChE), 3.70 ± 0.98 µM(for BuChE). Furthermore, the selected analogues considered for In-Vivo and cytotoxic study as well as structure modification carried out in search of more active analogues.

Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection.

Lecanemab (Leqembi©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

Lancao decoction in the treatment of alzheimer's disease via activating PI3K/AKT signaling to promote ERK involving in enhancing neuronal activities in the hippocampus

Ethnopharmacological relevancePrevious study has demonstrated lancao decoction (LC), a traditional Chinese medicine (TCM) fomula and recorded in “Huangdineijing”, has a therapeutic effect on cognitive impairment (early clinical manifestations of alzheimer's disease (AD), which suggests that LC may have potential therapeutic advantages for AD. Whether LC has the therapeutic effect on AD and its potential mechanisms were still further indicated. Aim of the studyIn this study, we aimed to uncover the potential advantage and neuronal mechanisms of LC in the treatment of AD in APP/PS1 mice in the hippocampus. Methods and materialsWe chose APP/PS1 mice to combing with behavioral tests including morris water maze (MWM) or y-maze to determine the role of LC in the therapeutic actions of AD. Network pharmacology was used to screen potential targets and pathways involving in LC’s treatments of AD. Western blot was used to detect the phosphorylated expressions of proteins in hippocampus in APP/PS1 mice in the hippocampus. Pharmacological interventions were used to elucidate the relationship between the role of LC in the treatment of AD and the pathway, as well as the upstream and downstream interactions with neuronal activities. ResultsAccording to our previous LC effective dose (2.5 g/kg), the dose was also able to significantly reduce the latency to the platform, and significantly increase the number of crossing times and time spend in the target quadrant in APP/PS1 mice in MWM, which was consistent with donepezil (DON) after 14 days chronic treatments. Network pharmacology showed that PI3K/AKT and MAPK pathways were closely associated with LC’s treatments of AD, and protein autophosphorylation played a role in this process. The phosphorylated expressions of PI3K and AKT were obviously reduced in APP/PS1 mice in the hippocampus, which were both reversed by LC or DON. The phosphorylated expressions of MAPK including P38, JNK and ERK were also significantly reduced in APP/PS1 mice hippocampus, but only the phosphorylated expression of ERK was reversed by LC or DON. Inhibiting the activities of PI3K/AKT pathway by LY294002 blocked LC’s improvement of behavioral deficits in APP/PS1 mice, including reducing latency to platform and increasing the number of crossings time in MWM in APP/PS1 mice, which also blunted LC’s up-regulated phosphorylated expressions of PI3K, AKT and ERK in the hippocampus. Moreover, suppressing the activities of ERK by PD98059 also blocked LC’s improvement of AD-related behavioral deficits including decreasing latency to new arm and increasing time in new arm in y-maze test, which also inhibited LC’s enhancement of synaptic proteins (PSD95 and synapsin1) in the hippocampus and the number of EGR1-positive cells in the hippocampal dentate gyrus (DG). ConclusionsTake together, our study revealed that LC had the therapeutic effects on AD by activating the PI3K/AKT pathway to enhance ERK activity and further strengthened neuronal activities in the hippocampus.

Application of mitochondrial miRNA-204 nanoprobes in Alzheimer's disease treatment by clearing reactive oxygen species-mediated autophagy

Neuronal mitochondrial damage is the primary characteristic of Alzheimer's disease (AD); as mitochondrial microRNAs (miRNAs) are crucial for maintaining mitochondrial function, developing a detection system for mitochondrial miRNAs and applying it for AD treatment is of great significance. Herein, we report CeO2-DNA-RNA hybrid chain (DRP)/mitochondrial aptamers (MA) nanoclusters, formed using specially modified 5 nm sized cerium dioxide (CeO2) nanoparticles, to achieve AD diagnosis and treatment by targeting mitochondrial miRNA-204. First, nanomaterials with unique reactive oxygen species-scavenging functions could easily enter the central nervous system, and surface modification with mitochondrial aptamers facilitated successful mitochondrial targeting. Furthermore, surface modification of nanomaterials with DNA-RNA hybrid biological detection probes was used to detect miRNA-204 in AD and simultaneously perform gene-silencing therapy. In 3 × Tg-AD model mice, CeO2-DRP/MA aggregated into neuronal mitochondria, silenced mitochondrial miRNA-204, and restored the damaged mitochondria for AD treatment. The promising diagnostic and therapeutic functions of CeO2-DRP/MA demonstrate its better performance as a diagnostic and therapeutic system targeting mitochondrial miRNA.

Current Bioactive Compounds in the Treatment of Alzheimer's Disease

Abstract: Worldwide, more than 44 million individuals are living with Alzheimer's disease (AD), making it the most common type of dementia. Because neuroinflammation is so important in the development of AD, anti-inflammatory tactics may be a promising avenue for treatment. Searches were conducted in Scopus, the Web of Science, and PubMed using the following keywords: phytoconstituents, AD, traditional medicine, and Chinese herbs. Therefore, the purpose of this review was to summarise the known phytochemistry and current state of the chosen plant species. However, there has been limited effectiveness in clinical trials for AD with currently available anti-inflammatory medicines. This study brings together the latest findings in the treatment of AD using natural substances, specifically phytochemicals, which have anti-inflammatory, antioxidant, and neuroprotective characteristics. Although there has been little success with existing anti-inflammatory medications, there is hope for targeting molecular pathways associated with AD, including Aβ overproduction, apoptosis, oxidative stress, and mitochondrial dysfunction, through the use of natural bioactive chemicals such alkaloids, polyphenols, and terpenes. The promise of natural compounds as safer alternatives or supplementary therapies to current treatments for Alzheimer's disease is highlighted in this study, which focuses on their ability to alleviate major pathogenic processes in the disease. Their medicinal potential and effectiveness can be enhanced with additional research.