Cause Of Dementia Research Articles

Epigenetics in the Development of Alzheimer’s Disease

Alzheimer's Disease (AD), a cause of dementia, has emerged as a significant public health concern that affects societies worldwide. Statistics of 2021 reveal that there are 55 million reported cases of this disease globally, this disease is characterized by the gradual deterioration of nerve cells in the brain, which inevitably leads to a decline in cognitive abilities. The progression of AD is significantly influenced by genetic factors. Scientific research has helped identify over 40 genetic risk loci that are associated with the disease, giving an idea on the molecular mechanisms behind its development. However, environmental factors and epigenetic modifications, which are changes in gene expression not caused by alterations in the DNA sequence, also play important roles in the disease's development and progression. The current treatment strategies for AD primarily aim to manage the symptoms and slow the rate of cognitive decline, but these treatments are not curative and the disease continues to progress. This underlines the importance of early diagnosis, which can significantly improve the effectiveness of these treatments. Decoding the role of genetics and epigenetics in the development of AD is key to identifying potential therapeutic targets and developing effective treatments. The understanding of these factors will provide valuable insights into the pathophysiology of AD, contributing to advancements in medical research and healthcare strategies aimed at combating the disease.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

An Overview of Etiology, Pathophysiology, and Promising Herbal Remedy for Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive brain disease that gradually reduces a person’s ability to think clearly, remember things, and even carry out simple cognitive tasks. It is the most common cause of dementia among the elderly. Although the exact cause is still unknown, genetic factors account for 5 to 10% of instances having a family origin. The damage leads to significant degeneration of the afflicted areas, resulting in memory loss, impaired capacity to acquire new knowledge, fluctuations in mood, difficulties in cognitive functioning, and an inability to do basic everyday tasks. However, it is still commonly acknowledged as the primary reason of dementia worldwide. The two chief pathological landscapes of AD are the build-up of substances outside the cells and the formation of twisted fibers within the cells, known as neurofibrillary tangles. Accumulation of Aβ amyloid (Aβ) initiates neurodegeneration, leading to the development of clinical dementia, which is a defining feature of AD.

Investigating Cortical Complexity in Mixed Dementia through Nonlinear Dynamic Analyses: A Resting-State EEG Study.

Objective: Dementia is a broad term referring to a decline in problem-solving abilities, language skills, memory, and other cognitive functions to a degree that it significantly disrupts everyday activities. The underlying cause of dementia is the impairment or loss of nerve cells and their connections within the brain. The particular symptoms experienced are contingent upon specific regions of the brain affected by this damage. In this research, we aimed to investigate the nonlinear dynamics of the mixed demented brain compared to healthy subjects using electroencephalogram (EEG) analysis. Method : For this purpose, EEG was recorded from 66 patients with mixed dementia and 65 healthy subjects during rest. After signal preprocessing, sample entropy and Katz fractal dimension analyses were applied to the preprocessed EEG data. Analysis of variance with repeated measures was utilized to compare the nonlinear dynamics of brain activity between dementia and healthy states and partial correlation analysis was employed to explore the relationship between EEG complexity measures and cognitive and neuropsychiatric symptoms of patients. Results: Based on repeated measures ANOVA, there was a significant main effect between groups for both Katz fractal dimension (F = 4.10, P = 0.01) and sample entropy (F = 4.81, P = 0.009) measures. Post hoc comparisons revealed that EEG complexity was significantly reduced in dementia mainly in the occipitoparietal and temporal areas (P < 0.05). MMSE scores were positively correlated with EEG complexity measures, while NPI scores were negatively correlated with EEG complexity measures, mainly in the occipitoparietal and temporal areas (P < 0.05). Moreover, using a KNN classifier, all significant complexity measures yielded the best classification performance with an accuracy of 98.05%, sensitivity of 97.03% and specificity of 99.16% in detecting dementia. Conclusion: This study demonstrated a unique dynamic system within the brain impacted by dementia that results in more predictable patterns of cortical activity mainly in the occipitoparietal and temporal areas. These abnormal patterns were associated with patients' cognitive capacity and neuropsychiatric symptoms.

Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β

Alzheimer’s disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure–activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 μM), although the potency was increased by 2′ substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC50 = 0.0021 μM), and the electron-withdrawing group and 2′ and 3′ substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14–35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.

Advances in blood biomarkers for Alzheimer disease (AD): A review.

Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out-of-pocket costs, perceived risks, and the lack of AD-specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non-invasive and cost-effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aβ) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed.

From Gut Microbiota to Brain Waves: The Potential of the Microbiome and EEG as Biomarkers for Cognitive Impairment.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and a leading cause of dementia. Aging is a significant risk factor for AD, emphasizing the importance of early detection since symptoms cannot be reversed once the advanced stage is reached. Currently, there is no established method for early AD diagnosis. However, emerging evidence suggests that the microbiome has an impact on cognitive function. The gut microbiome and the brain communicate bidirectionally through the gut-brain axis, with systemic inflammation identified as a key connection that may contribute to AD. Gut dysbiosis is more prevalent in individuals with AD compared to their cognitively healthy counterparts, leading to increased gut permeability and subsequent systemic inflammation, potentially causing neuroinflammation. Detecting brain activity traditionally involves invasive and expensive methods, but electroencephalography (EEG) poses as a non-invasive alternative. EEG measures brain activity and multiple studies indicate distinct patterns in individuals with AD. Furthermore, EEG patterns in individuals with mild cognitive impairment differ from those in the advanced stage of AD, suggesting its potential as a method for early indication of AD. This review aims to consolidate existing knowledge on the microbiome and EEG as potential biomarkers for early-stage AD, highlighting the current state of research and suggesting avenues for further investigation.

Current understanding of Alzheimer's disease

Worldwide, and disproportionately among the aged, Alzheimer's disease (AD) is a neurological disease that worsens over time and is the main cause of dementia. It begins with a gradual loss of cognitive abilities and memory, progresses to changes in behavior, and culminates in the death of neurons and dementia. A number of promising novel AD therapies, however, are in the works. This article summarizes current theories on the origin of Alzheimer's disease and focuses on recent developments in treatment, including immunotherapy, gene therapy, peptidomimetics, metal chelators.

Chasing shadows: Investigating X chromosome mediation in late-onset Alzheimer’s disease

Alzheimer&amp;rsquo;s disease (AD) is a major cause of dementia. While maternal inheritance has been recognized for late-onset AD (LOAD), risk factors have not been identified consistently on the X chromosome. We recently developed a new method to identify an apparent risk of 70% mediated by the X chromosome in newly-presenting cognitive disorders clinic patients with amnestic mild cognitive impairment (aMCI) or early LOAD with unilateral parental lineage for AD or dementia. We sought to confirm our preliminary findings in the Utah Population Database (UPDB). We obtained previously published aggregate data on the risk of AD in the UPDB based on family history, stratified the data by the sex of the proband, and analyzed them using the new method. The X chromosome-attributable relative risk was estimated by calculating the following: Odds ratio (OR) = (women with paternal lineage: Women with maternal lineage)/(men with paternal lineage: Men with maternal lineage). The proportion of genetic risk attributable to the X chromosome is equal to (OR-1)/OR. The analysis did not reveal any risk mediated by the X chromosome, and the null result could be attributed to methodological limitations. Factors that impact the initial or early presentation (incidence) of LOAD, which are appropriate for consideration as risk factors, may not be detectable in a (prevalent) population of deceased individuals. Thus, epidemiological evidence for the contribution of the X chromosome to the development of LOAD will need to be sought prospectively in incident patient populations with newly diagnosed, biologically-confirmed aMCI or LOAD.

Altered glia-neuron communication in Alzheimer’s Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq

BackgroundAlzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not significantly differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.

Piracetam reduces oxidative stress and mitochondrial function impairment in an in vitro model of vascular dementia.

Vascular dementia (VaD) is the most common cause of dementia in older adults. Due to the lack of effective treatment options, there is an urgent need to find an effective pharmaceutical compound to combat VaD. Piracetam has been reported to improve impaired cognitive function in a variety of conditions in both human and animal models. However, the role and mechanism of Piracetam in VaD remain unclear. Therefore this study aimed to elucidate the effect of Piracetam on a cellular model of VaD in vitro. We found that Piracetam enhanced the growth of OGD-stimulated SH-SY5Y cells. In addition, Piracetam inhibited the oxidative stress of OGD-stimulated SH-SY5Y cells. Further, Piracetam improved mitochondrial function of OGD-stimulated SH-SY5Y cells. Mechanistically, Piracetam inhibited the PI3K/Akt/mTOR pathway in OGD-stimulated SH-SY5Y cells. Collectively, Piracetam improved oxidative stress and mitochondrial dysfunction of OGD-stimulated SH-SY5Y cells through PI3K/Akt/mTOR axis. Hence, Piracetam has the potential to serve as a promising drug of VaD.

IPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells(PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.

Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs.

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.

ANALYZE-AD: A comparative analysis of novel AI approaches for early Alzheimer’s detection

Alzheimer’s disease, characterized by progressive and irreversible deterioration of cognitive functions, represents a significant health concern, particularly among older adults, as it stands as the foremost cause of dementia. Despite its debilitating nature, early detection of Alzheimer’s disease holds considerable advantages for affected individuals. This study investigates machine-learning methodologies for the early diagnosis of Alzheimer’s disease, utilizing datasets sourced from OASIS and ADNI. The initial classification methods consist of a 5-class ADNI classification and a 3-class OASIS classification. Three unique methodologies encompass binary-class inter-dataset models, which involve training on a single dataset and subsequently testing on another dataset for both ADNI and OASIS datasets. Additionally, a hybrid dataset model is also considered. The proposed methodology entails the concatenation of both datasets, followed by shuffling and subsequently conducting training and testing on the amalgamated dataset. The findings demonstrate impressive levels of accuracy, as Light Gradient Boosting Machine (LGBM) achieved a 99.63% accuracy rate for 5-class ADNI classification and a 95.75% accuracy rate by Multilayer Perceptron (MLP) for 3-class OASIS classification, both when hyperparameter tweaking was implemented. The K-nearest neighbor algorithm demonstrated exceptional performance, achieving an accuracy of 87.50% in ADNI-OASIS (2 Class) when utilizing the Select K Best method. The Gaussian Naive Bayes algorithm demonstrated exceptional performance in the OASIS-ADNI approach, attaining an accuracy of 77.97% using Chi-squared feature selection. The accuracy achieved by the Hybrid method, which utilized LGBM with hyperparameter optimization, was 99.21%. Furthermore, the utilization of Explainable AI approaches, particularly Lime, was implemented in order to augment the interpretability of the model.

Synthesis and Biological Evaluation of 2-Amino-1-phenyl-benzimidazole Derivatives as BACE1 Inhibitors

Background: Alzheimer’s disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of β-amyloid (Aβ) is considered the main pathogenies of AD, and β-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of Aβ. Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenylbenzimidazole derivatives were designed and synthesized in this work. Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1~T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized. Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC50 = 0.45 μM), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93. Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.

Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

Alzheimer’s disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aβ42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

Artesunate improves learning and memory impairment in rats with vascular cognitive impairment by down-regulating the level of autophagy in cerebral cortex neurons

BackgroundVascular cognitive impairment (VCI) is the second leading cause of dementia. Cognitive impairment is a common consequence of VCI. However, there is no effective treatment for VCI and the underlying mechanism of its pathogenesis remains unclear. This study to investigate whether artesunate (ART) can improve the learning and memory function in rats with VCI by down-regulating he level of autophagy in cerebral cortex neurons. MethodsThe models for VCI were the rat bilateral common carotid artery occlusion (BACCO), which were randomized into three groups including the sham operation group (Sham), model + vehicle group (Model) and model + ART group (ART). Then the animal behaviors were recorded, as well as staining the results of cortical neurons. Western blot was performed to determine the protein expressions of LC3BⅡ/Ⅰ, p-AMPK, p-mTOR, and Beclin-1. ResultsBehavioral outcomes and the protein expressions in Model group were supposedly affected by the induction of autophagy in cerebral cortex neurons. Compared to the Model group, ART improved memory impairment in VCI rats. And the expression of LC3BⅡ/Ⅰ, p-AMPK/AMPK, Beclin-1 is significant decreased in the ART group, while significant increases of p-mTOR/mTOR were showed. These results suggest that ART improved learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons. ConclusionThe results suggest that autophagy occurs in cerebral cortex neurons in rats with VCI. It is speculated that ART can improve learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons.

Olfactory Dysfunction and Alzheimer's Disease: A Review.

Alzheimer's disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer's disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer's disease. While a correlation between olfactory dysfunction and Alzheimer's disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer's disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer's disease including amyloid-β protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction.

A Comprehensive Analytical Review of Polyphenols: Evaluating Neuroprotection in Alzheimer's Disease.

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, is the primary cause of dementia. Despite significant advancements in neuroscience, a definitive cure or treatment for this debilitating disease remains elusive. A notable characteristic of AD is oxidative stress, which has been identified as a potential therapeutic target. Polyphenols, secondary metabolites of plant origin, have attracted attention due to their potent antioxidant properties. Epidemiological studies suggest a correlation between the consumption of polyphenol-rich foods and the prevention of chronic diseases, including neurodegenerative disorders, which underscores the potential of polyphenols as a therapeutic strategy in AD management. Hence, this comprehensive review focuses on the diverse roles of polyphenols in AD, with a particular emphasis on neuroprotective potential. Scopus, ScienceDirect, and Google Scholar were used as leading databases for study selection, from 2018 to late March 2024. Analytical chemistry serves as a crucial tool for characterizing polyphenols, with a nuanced exploration of their extraction methods from various sources, often employing chemometric techniques for a holistic interpretation of the advances in this field. Moreover, this review examines current in vitro and in vivo research, aiming to enhance the understanding of polyphenols' role in AD, and providing valuable insights for forthcoming approaches in this context.

Generation of Alzheimer's Disease Model Derived from Induced Pluripotent Stem Cells with APP Gene Mutation.

Alzheimer's disease (AD), the most common cause of dementia, is characterized by disruptions in memory, cognition, and personality, significantly impacting morbidity and mortality rates among older adults. However, the exact pathophysiological mechanism of AD remains unknown, and effective treatment options for AD are still lacking. Human induced pluripotent stem cells (iPSC) are emerging as promising platforms for disease research, offering the ability to model the genetic mutations associated with various conditions. Patient-derived iPSCs are useful for modeling neurodegenerative and neurodevelopmental disorders. In this study, we generated AD iPSCs from peripheral blood mononuclear cells obtained from a 65-year-old patient with AD carrying the E682K mutation in the gene encoding the amyloid precursor protein. Cerebral organoids derived from AD iPSCs recapitulated the AD phenotype, exhibiting significantly increased levels of tau protein. Our analysis revealed that an iPSC disease model of AD is a valuable assessment tool for pathophysiological research and drug screening.