Cognitive Loss Research Articles

UAV Swarm Rounding Strategy Based on Deep Reinforcement Learning Goal Consistency with Multi-Head Soft Attention Algorithm

Aiming at the problem of target rounding by UAV swarms in complex environments, this paper proposes a goal consistency reinforcement learning approach based on multi-head soft attention (GCMSA). Firstly, in order to make the model closer to reality, the reward function when the target is at different positions and the target escape strategy are set, respectively. Then, the Multi-head soft attention module is used to promote the information cognition of the target among the UAVs, so that the UAVs can complete the target roundup more smoothly. Finally, in the training phase, this paper introduces cognitive dissonance loss to improve the sample utilization. Simulation experiments show that GCMSA is able to obtain a higher task success rate and is significantly better than MADDPG in terms of algorithm performance.

Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β.

Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively. We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β. Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies. Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.

NAD+ supplement relieved chronic sleep restriction (CSR)-induced microglial proinflammation in vivo and in vitro

Sleep insufficiency is a significant health problem worldwide and can induce multiple neurodevelopmental disorders in the central nervous system (CNS). Sleep deprivation (SD), especially chronic SD, leads to cognition and memory loss and worsens neurodegenerative disease liability. Microglia are the main inflammation-dominant glia and play a crucial role in SD-induced neurological impairments. Nicotinamide adenine dinucleotide (NAD+) is a redox reaction coenzyme that exerts anti-inflammatory and mitochondria-protective effects in microglia. Whether NAD+ mitigated SD-induced neurological disorders by regulating microglial functions is still unknown. In the current study, we designed an in vivo and in vitro model to evaluate the neuroprotective effect of NAD+ on chronic sleep restriction (CSR) and further investigate the underlying mechanisms. Behavioral tests and immunofluorescence staining were applied to investigate the cognition impairments and microglial activation. Biochemical experiments were tested to analyze the oxidative status and possible mechanism. In vitro data were used to verify the in vivo data. Our results displayed that NAD+ supplement mitigated CSR-induced cognitive decline and microglial activation response by suppressing the expression of pro-inflammatory cytokines in vivo. NAD+ administration also decreased oxidative stress and mitochondrial impairments in microglia. In vitro results showed that NAD+ treatment inhibited ROS production and prompted M1 conversion to M2 phenotype. cGAS-STING/NF-κB pathways were significantly activated but down-regulated by NAD+ administration. H151, a STING antagonist, was applied to validate that NAD+ treatment alleviates neuroinflammation partially by regulating cGAS-STING pathways in microglia. Our findings suggest that NAD+ supplement is a promising therapy for sleep disorders-induced neurological problems, and cGAS-STING pathway may act as a critical regulator in microglial proinflammation.

Correction: Perceived cognitive loss, symptomology, and psychological well-being with bipolar disorder

Correction: Perceived cognitive loss, symptomology, and psychological well-being with bipolar disorder

Exosomal mRNA Signatures as Predictive Biomarkers for Risk and Age of Onset in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. While the precise causes of AD remain unclear, emerging evidence suggests that messenger RNA (mRNA) dysregulation contributes to AD pathology and risk. This study examined exosomal mRNA expression profiles of 15 individuals diagnosed with AD and 15 healthy controls from Barranquilla, Colombia. Utilizing advanced bioinformatics and machine learning (ML) techniques, we identified differentially expressed mRNAs and assessed their predictive power for AD diagnosis and AD age of onset (ADAOO). Our results showed that ENST00000331581 (CADM1) and ENST00000382258 (TNFRSF19) were significantly upregulated in AD patients. Key predictors for AD diagnosis included ENST00000311550 (GABRB3), ENST00000278765 (GGTLC1), ENST00000331581 (CADM1), ENST00000372572 (FOXJ3), and ENST00000636358 (ACY1), achieving > 90% accuracy in both training and testing datasets. For ADAOO, ENST00000340552 (LIMK2) expression correlated with a delay of ~12.6 years, while ENST00000304677 (RNASE6), ENST00000640218 (HNRNPU), ENST00000602017 (PPP5D1), ENST00000224950 (STN1), and ENST00000322088 (PPP2R1A) emerged as the most important predictors. ENST00000304677 (RNASE6) and ENST00000602017 (PPP5D1) showed promising predictive accuracy in unseen data. These findings suggest that mRNA expression profiles may serve as effective biomarkers for AD diagnosis and ADAOO, providing a cost-efficient and minimally invasive tool for early detection and monitoring. Further research is needed to validate these results in larger, diverse cohorts and explore the biological roles of the identified mRNAs in AD pathogenesis.

Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.

Alzheimer's disease (AD) is characterized by cognitive decline and memory loss, involving mechanisms such as tau hyperphosphorylation and mitochondrial dysfunction. Increasing evidence suggests that age-related alterations in metabolite levels are crucial for the pathogenesis of AD. Here, we analyzed serum metabolites from mice of various ages (2, 4, 14, and 21 months old) using mass spectrometry. We identified palmitoyl-L-carnitine as a key metabolite with significantly increased levels in aged mice. In vitro experiments with SH-SY5Y neuronal cells demonstrated that palmitoyl-L-carnitine treatment enhanced tau phosphorylation, increased mitochondrial fission, and elevated intracellular calcium levels. Furthermore, the increased levels of tau phosphorylation were significantly reduced by the inhibition of GSK-3β, CDK5, and calpain, indicating that tau kinases activated by calcium overload are directly involved in the increase of tau phosphorylation. Considering that mitochondrial fission is related to mitochondrial dysfunction, we propose that the elevated level of serum palmitoyl-L-carnitine during aging contributes to AD pathology through these pathways. These findings highlight the significant role of lipid metabolism in neurodegeneration and offer potential therapeutic targets for age-related diseases, including AD.

The Present Difficulties and Potential Benefits of Dopaminergic Agents in Parkinson's Disease Treatment

Parkinson's disease (PD) is a progressive neurological condition characterized by bradykinesia, rigidity, tremors, and impaired balance, among other motor impairments. The issue arises from dopaminergic neurons located in the spinal column of the brain. This research report examines the therapeutic potential of dopaminergic medications in the management of Parkinson's disease. The central concept of Parkinson's disease (PD) revolves around the notion that dopaminergic pathways exert significant influence over the regulation of movement. The book examines various dopaminergic medications, elucidating their mechanisms of action and the impact they exert on dopamine signaling. Examples of these medications include levodopa, dopamine agonists, and monoamine oxidase-B (MAO-B) inhibitors. Although dopaminergic medicines initially aid in the treatment of Parkinson's disease (PD), prolonged usage of these medications gives rise to several complications. Experiencing dyskinesias and motor fluctuations, characterized by episodes of involuntary movements and behaviors that are undesired, is a significant challenge. This study investigates the underlying causes of these difficulties and explores potential treatment options, including the use of controlled-release formulations and further therapy. The book discusses the non-motor symptoms of Parkinson's disease (PD), as well as the use of dopaminergic medications to treat mood disorders, autonomic dysfunction, and cognitive loss. Dopaminergic medications remain crucial in reducing motor symptoms and enhancing the quality of life for those with Parkinson's disease. Parkinson's disease (PD) is a complex condition with multiple distinct variations. In order to address its existing challenges and explore its potential implications for future Parkinson's disease medications, a comprehensive and effectively coordinated strategy is required.

Human herpesvirus 6 (HHV-6) encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapy.

Human herpesvirus (HHV)-6 encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapyis relatively rare in clinical practice and needs to be differentiated from immune effector cell-associatedneurotoxicity syndrome (ICANS). We retrospectively reported a case of HHV-6 encephalitis secondary to CAR-T cell therapy. A male patient from China with diffuse large B-cell lymphoma underwent chimeric CAR-T cell therapy anddeveloped a generalized rash on the 8th day, followed by cognitive changes, memory loss, and disorientation onthe 14th day after CAR-T cell therapy. Initially, ICANS was suspected. A lumbar puncture was performed on the 18th day. The cerebrospinal fluid (CSF) analysis revealed slightly elevated protein levels and a high presence of HHV-6B sequences by mNGS. Brain MRI showed bilateral hippocampal abnormalities. The patient was ultimatelydiagnosed with HHV-6 encephalitis and treated with ganciclovir and dexamethasone. After one week of treatment,follow-up CSF analysis showed a reduction in HHV-6B sequences. The patient was discharged with improvedmemory and orientation. HHV-6 encephalitis secondary to CAR-T cell therapy may be easily confused with ICANS. Timely andaggressive diagnostic procedures, such as mNGS of CSF and cranial imaging, along with prompt antiviral therapy,are crucial for improving patient outcomes.

Explainable AI for Alzheimer Detection: A Review of Current Methods and Applications

Alzheimer’s disease (AD) is the most common cause of dementia, marked by cognitive decline and memory loss. Recently, machine learning and deep learning techniques have introduced promising solutions for improving AD detection through MRI, especially in settings where specialists may not be readily available. These techniques offer the potential to assist general practitioners and non-specialists in busy clinical environments. However, the ‘black box’ nature of many AI techniques makes it challenging for non-expert physicians to fully trust their diagnostic accuracy. In this review, we critically evaluate current explainable AI (XAI) methods applied to AD detection and highlight their limitations. In addition, a new interpretability framework, called “Feature-Augmented”, was theoretically designed to improve model interpretability. This approach remains underexplored, primarily due to the scarcity of explainable AD-specific datasets. Furthermore, we underscore the importance of AI models being accurate and explainable, which enhance diagnostic confidence and patient care outcomes.

Synthesis, biological evaluation and in silico study of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxy coumarin as acetylcholinesterase inhibitors

Alzheimer’s disease, characterized by cognitive decline and memory loss, is associated with decreased acetylcholine levels due to acetylcholinesterase (AChE) activity. Compounds containing a coumarin heterocyclic core coupled with thiazole exhibit excellent acetylcholinesterase inhibitory activity. In this work, we designed and synthesized a series of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxycoumarin. The compounds were synthesized and their inhibitory activities were evaluated through in vitro biological assays. Of the compounds investigated, 3i exhibited the strongest inhibitory activity, with an IC50 value of 2.7 µM. Molecular docking and molecular dynamics simulations were employed to elucidate the binding interactions and stability of the synthesized compounds with AChE. The results demonstrated promising inhibitory activity, suggesting potential therapeutic applications for Alzheimer’s disease. This research contributes to the development of coumarin-based heterocyclic compounds as effective AChE inhibitors.

Cutting-Edge Strategies for Overcoming Therapeutic Barriers in Alzheimer's Disease.

Alzheimer's disease (AD) remains one of the hardest neurodegenerative diseases to treat due to its enduring cognitive deterioration and memory loss. Despite extensive research, few viable treatment approaches have been found; these are mostly due to several barriers, such as the disease's complex biology, limited pharmaceutical efficacy, and the BBB. This presentation discusses current strategies for addressing these therapeutic barriers to enhance AD treatment. Innovative drug delivery methods including liposomes, exosomes, and nanoparticles may be able to pass the blood-brain barrier and allow medicine to enter specific brain regions. These innovative strategies of medicine distribution reduce systemic side effects by improving absorption. Moreover, the development of disease-modifying treatments that target tau protein tangles, amyloid-beta plaques, and neuroinflammation offers the chance to influence the course of the illness rather than only treat its symptoms. Furthermore, gene therapy and CRISPR-Cas9 technologies have surfaced as potentially groundbreaking methods for addressing the underlying genetic defects associated with AD. Furthermore, novel approaches to patient care may involve the utilization of existing medications having neuroprotective properties, such as those for diabetes and cardiovascular conditions. Furthermore, biomarker research and personalized medicine have made individualized therapy approaches possible, ensuring that patients receive the best care possible based on their unique genetic and molecular profiles.

Investigating the Potential Impact of LH on the Progression of Alzheimer’s Disease via Microglia Activation and C/EBPβ pathway

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that causes irreversible cognitive decline and memory loss. The disproportionate effect of AD on postmenopausal women prompts investigation into the role of hormonal changes in disease pathogenesis. However, previous studies on estrogen replacement therapies have shown inconsistent results. Therefore, further confirmation is needed to ensure the independent effects of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on AD pathology. Our study will 1) focus on microglial activation pathway 2) focus on the LH-C/EBPβ-AEP pathway and its potential influence on AD progression.Methods: Using cell lines to investigate whether microglial activation is present. HMC3 cells will be treated with LH or control phosphate buffered saline (PBS). Carry out Western Blot (WB) and qPCR to confirm presence of cytokines, which is the product of microglial activation. Using 3xTg-AD mice treated with LH or control PBS. To identify AD progression, immunofluorescent (IF) micrograph will be used to quantify amyloid-beta (Aβ) load. WB and qPCR will be used to identify cytokines. Morris water maze (MWM) will be carried out for cognitive testing. Using an ovariectomized mice model to investigate the LH-C/EBPβ-AEP pathway. Mice will be treated with LH antibodies or control IgG, followed by assessments using IVIS imaging and MWM test to measure spatial memory. IF, WB and qPCR will be used to quantify Aβ and Tau protein levels and gene expression changes. Furthermore, the study will explore the precise relationship between LH and C/EBPβ expression through inhibition experiments targeting AKT and ERK1/2 signaling pathways.Expected results: Our hypothesis is that LH activates microglia, with both pro-inflammatory and anti-inflammatory cytokine released. This change in microglia function suggests LH has an effect on microglia and hence removal of Aβ plaques. Another hypothesis is that LH antibody manages to cross the blood-brain barrier. The cognitive ability will be improved in LH-Ab treated mice with reduced Aβ and Tau protein levels and downregulation of the C/EBPβ–AEP/δ-secretase pathway. Simultaneously, we expect that there will be a positive correlation between LH levels and expression of C/EBPβ-related pathways, suggesting the involvement of AKT and ERK1/2 signaling pathways in AD progression.Conclusion: This study aims to provide evidence for the link between LH activation of the C/EBPβ pathway and AEP production, promoting our understanding of AD pathogenesis. The insights gained may implicate therapeutic strategies targeting LH mechanisms in postmenopausal women at risk of AD.

Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer's disease.

Dihydro-resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation-mediated injury. However, it is still unknown whether it has anti-neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD). The anti-inflammatory and anti-Alzheimer's disease actions of dihydro-resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open-field test. Flow cytometry assay, western blotting, immunofluorescence assays and co-immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy. In this study, in vivo observations indicated that the administration of dihydro-resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR-generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP-induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3-dependent mitophagy and ULK phosphorylation. In summary, these findings suggest that dihydro-resveratrol (DHR) possesses potent anti-neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD.

Sleep Disorders in Alzheimer’s Disease

Alzheimer’s disease is the leading cause of dementia worldwide. Patients typically exhibit cognitive impairment, memory loss, diminished social and occupational functioning, as well as language and motor disorders. Alzheimer’s disease is characterized by the abnormal accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. These pathological changes not only disrupt neuronal function and lead to cognitive deficits, but also interfere with sleep regulation, resulting in sleep disorders. Such disturbances can diminish nighttime sleep quality and contribute to daytime functional impairments, further exacerbating cognitive decline. Therefore, exploring the interplay between cognitive impairment, Alzheimer’s disease, and sleep disorders is crucial for enhancing the quality of life of Alzheimer’s patients. This review summarizes current literature on the interconnections among Alzheimer’s disease, cognitive impairment, and sleep disorders. Sleep disturbances are prevalent in Alzheimer’s patients and can also occur in those with amnestic mild cognitive impairment, which often precedes Alzheimer’s onset. Such sleep disorders may promote and accelerate the accumulation of amyloid-β and tau proteins [1-3]. Furthermore, Alzheimer’s patients may be more vulnerable to sleep disturbances, creating a potential vicious cycle. Further investigation into these relationships may provide valuable insights for the treatment or prevention of Alzheimer’s disease.

Late-onset caloric restriction improves cognitive performance and restores circadian patterns of neurotrophic, clock and epigenetic factors in the hippocampus of male old rats.

Aging is a complex multifactorial process that results in a general functional decline, including cognitive impairment. Caloric restriction (CR) can positively influence the aging processes and delay cognitive decline. There is a rhythmic variation in memory and learning processes throughout the day, indicating the involvement of the circadian clock in the regulation of these processes. Despite growing evidence on the efficacy of CR, it has not yet been fully determined whether starting this strategy at an advanced age is beneficial for improving quality of life and eventually, for protection against age-related diseases. Here, we investigated the effect of late-onset CR on the temporal organization of the molecular clock machinery, molecules related to cognitive processes and epigenetic regulation, in the hippocampus of male old rats maintained under constant darkness conditions. Our results evidenced the existence of a highly coordinated temporal organization of Bmal1, Clock, Bdnf, Trkb, Dnmts, Sirt1, and Pgc-1α in the hippocampus of young adult rats. We observed that aging led to cognitive deficits and loss of circadian oscillations of all the above variables. Interestingly, CR restored circadian rhythmicity in all cases and, in addition, improved the cognitive performance of the old animals. This work would highlight the importance of the circadian clock and its synchronization with feeding signals, as the basis of the beneficial effects of CR. Thus, lifestyle modifications, such as CR, might be a powerful intervention to preserve hippocampal circadian organization and cognitive health during aging.

Green synthesis of Tacrine modified Schiff bases as anti-Alzheimer Agents: An effective strategy validated through in-silico and in-vitro analysis

A variety of Tacrine-modified Schiff base analogues were developed via solvent free (green) method and structurally elucidated using 1HNMR, FTIR and UV–Vis analysis. High product yield was obtained from the synthesised molecules, which were produced efficiently at room temperature without the need of a solvent. The developed molecules were subsequently assessed for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These molecules revealed effective inhibition of AChE and BChE enzymes with IC50 values varying from 0.1 ± 0.02 to 0.3 ± 0.03 μM and 0.065 ± 0.01 to 0.3 ± 0.03 μM respectively. Compared to the standard Tacrine which has IC50 values of 0.35 ± 0.02 μM for AChE and 0.1 ± 0.01 μM for BChE. Notably, compound 3f showed strong inhibition among others for both the enzymes. The structure–activity relationship of derivatives synthesized were verified and established through molecular docking studies. Theoretical ADME studies also predicted excellent drug-likeness for all the synthesized molecules. Antioxidant activities were also assessed because elevated oxidative stress levels are linked with cognitive loss in Alzheimer's disease (AD). These findings suggest that the lead compound is potentially an effective inhibitor for the therapeutic management of AD.

Advances and Challenges in Gene Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD.

Correlation between iron deposition and cognitive function in mild to moderate Alzheimer's disease based on quantitative susceptibility mapping.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressively worsening cognitive decline and memory loss. Excessive iron accumulation produces severe cognitive impairment. However, there are no uniform conclusions about changes in brain iron content in AD. This study aimed to investigate the iron content of the deep brain nuclei in AD, and its correlation with cognitive function. Thirty-one patients with mild to moderate AD, 17 patients with mild cognitive impairment (MCI), and 20 age-, sex-, and education-matched healthy controls (HC) were collected. The QSM was used to quantify the magnetic susceptibility values of the caudate nucleus, putamen, globus pallidus, substantia nigra, red nucleus, and dentate nucleus, and to analyze the differences that existed between the three groups. As well as the correlation between the magnetic susceptibility values and cognitive function was calculated. The magnetic susceptibility values of bilateral globus pallidus, left putamen, and bilateral substantia nigra were significantly higher in AD patients than in HC, and the magnetic susceptibility values of the right globus pallidus were significantly higher in AD patients than in MCI (all p < 0.05). The magnetic susceptibility values of the left dentate nucleus in the AD group were negatively correlated with the writing function of the MMSE subitem (r = -0.42, p = 0.020), and the magnetic susceptibility values of the left caudate nucleus and right dentate nucleus were significantly and negatively correlated with the naming function and language function of the MoCA subitem, respectively (r = -0.43, p = 0.019; r = -0.36, p = 0.048). Magnetic susceptibility values based on QSM correlate with cognitive function are valuable in discriminating AD from MCI and AD from HC.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Novel Piperazine Based Compounds Target Alzheimer's Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein.

Alzheimer's disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ1-42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ1-42 as well as dissociation of preformed aggregates from these peptides. Compounds D-687 and D-688 reversed Aβ1-42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with Drosophila melanogaster expressing human tau protein isoform (2N4R) in all the neurons, compound D-688 significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.