Development Of Alzheimer's Disease Research Articles

ALZHEIMER HASTALIĞINDA iNOS İNHİBİTÖRLERİNİN UMUT VERİCİ ROLÜ

Objective: This study aims to explore the role of iNOS inhibitors in Alzheimer's disease (AD), a neurodegenerative disorder affecting millions worldwide. The main symptoms of AD include memory loss, cognitive decline, and behavioral changes. While the exact cause remains uncertain, both genetic and environmental factors are believed to contribute. Recent research has emphasized the significance of nitric oxide (NO) in AD development. Specifically, the upregulation of inducible nitric oxide synthase (iNOS) in AD patients leads to excessive NO production during neuronal inflammation, exacerbating AD and dementia. Therefore, the investigation focuses on the potential of iNOS inhibitors as a novel therapeutic approach for AD treatment. Result and Discussion: In this review, we present the current therapeutic strategies available for Alzheimer's disease (AD) and explore the promising potential of iNOS inhibitors in AD treatment. Specifically, we will focus on their capacity to mitigate NO production and examine their potential neuroprotective effects. Additionally, this review will offer an overview of both natural and synthetic iNOS inhibitors, emphasizing the importance of safety considerations during the development of iNOS inhibitors as therapeutic interventions for AD.

Alzheimer's disease and epilepsy: shared neuropathology guides current and future treatment strategies.

Epilepsy is a cause of profound disability in patients with Alzheimer's disease (AD). The risk of being diagnosed with AD increases the risk for epilepsy, and in parallel, a history of epilepsy increases the likelihood of the development of AD. This bi-directional relationship may be due to underlying shared pathophysiologic hallmarks, including decreased cerebrospinal fluid amyloid beta 42 (Aβ42), increased hyperphosphorylated tau protein, and hippocampal hyperexcitability. Additionally, there are practical treatment considerations in patients with co-morbid AD and epilepsy-namely, there is a higher risk of seizures associated with medications commonly prescribed for Alzheimer's disease patients, including antidepressants and antipsychotics such as trazodone, serotonin norepinephrine reuptake inhibitors (SNRIs), and first-generation neuroleptics. Anti-amyloid antibodies like aducanumab and lecanemab present new and unique considerations in patients with co-morbid AD and epilepsy given the risk of seizures associated with amyloid-related imaging abnormalities (ARIA) seen with this drug class. Finally, we identify and detail five active studies, including two clinical trials of levetiracetam in the respective treatment of cognition and neuropsychiatric features of AD, a study characterizing the prevalence of epilepsy in AD via prolonged EEG monitoring, a study characterizing AD biomarkers in late-onset epilepsy, and a study evaluating hyperexcitability in AD. These ongoing trials may guide future clinical decision-making and the development of novel therapeutics.

The influence of epigenetic factors on the development of Alzheimer`s and Parkinson`s diseases

Alzheimer's and Parkinson's diseases continue to pose significant challenges in the field of neurodegenerative disorders, affecting millions of individuals worldwide. Over the past decades, it has become evident that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNA regulation, play a pivotal role in the pathogenesis of these diseases. In this article, we discuss recent scientific advancements in the study of epigenetic changes associated with Parkinson's and Alzheimer's diseases. We explore alterations in DNA methylation and their impact on the expression of genes related to neurodegeneration. Histone modifications, including acetylation and methylation, and their role in the regulation of genes associated with inflammation and amyloid proteins are also elucidated. Furthermore, we delve into the influence of microRNAs and non-coding RNAs on the pathogenesis of these diseases. Understanding the epigenetic mechanisms in Parkinson's and Alzheimer's diseases may shed light on new prospects for diagnosis, treatment, and prevention of these neurodegenerative disorders.

Bioinformatic Analysis and Experimental Validation of Ubiquitin-Proteasomal System-Related Hub Genes as Novel Biomarkers for Alzheimer's Disease.

Alzheimer's disease (AD) is a common progressive neurodegenerative disease. The Ubiquitin-Protease system (UPS), which plays important roles in maintaining protein homeostasis in eukaryotic cells, is involved in the development of AD. This study sought to identify differential UPS-related genes (UPGs) in AD patients by using bioinformatic methods, reveal potential biomarkers for early detection of AD, and investigate the association between the identified biomarkers and immune cell infiltration in AD. The differentially expressed UPGs were screened with bioinformatics analyses using the Gene Expression Omnibus (GEO) database. A weighted gene co-expression network analysis (WGCNA) analysis was performed to explore the key gene modules associated with AD. A Single-sample Gene Set Enrichment Analysis (ssGSEA) analysis was peformed to explore the patterns of immune cells in the brain tissue of AD patients. Real-time quantitative PCR (RT-qPCR) was performed to examine the expression of hub genes in blood samples from healthy controls and AD patients. In this study, we identified four UPGs (USP3, HECW2, PSMB7, and UBE2V1) using multiple bioinformatic analyses. Furthermore, three UPGs (USP3, HECW2, PSMB7) that are strongly correlated with the clinical features of AD were used to construct risk score prediction markers to diagnose and predict the severity of AD. Subsequently, we analyzed the patterns of immune cells in the brain tissue of AD patients and the associations between immune cells and the three key UPGs. Finally, the risk score model was verified in several datasets of AD and showed good accuracy. Three key UPGs are identified as potential biomarker for AD patients. These genes may provide new targets for the early identification of AD patients.

The neuroprotective effects of Liuwei Dihuang medicine in the APP/PS1 mouse model are dependent on the PI3K/Akt signaling pathway.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that progressively impairs cognitive function and memory. The occurrence and development of Alzheimer's disease involves many processes. In response to the complex pathogenesis of AD, the Traditional Chinese medicine formula Liuwei Dihuang Pill (LWD) has been shown to improve the cognitive function of AD animal models. However, the active ingredients and mechanism of action of LWD have not been fully elucidated. In this study, network pharmacological analysis predicted 40 candidate compounds in LWD, acting on 227 potential targets, of which 185 were associated with AD. Through network pharmacological analysis, the mechanism of action of LWD therapy AD is related to the inhibition of inflammatory response, regulation of neuronal state, and autophagy. In this experiment, LWD was detected in the APP/PS1 transgenic mouse model. The objective was to observe the effects of LWD on hippocampal learning and memory ability, Aβ clearance, autophagy and inflammatory response in APP/PS1 mice. The results showed that LWD improved long-term memory and working memory in APP/PS1 mice compared with the WT group. At the same time, LWD can increase the expression of hippocampal autophagy biomarkers, reduce the precipitation of Aβ, and the activation of microglia and astrocytes. Its mechanism may be related to the regulation of the PI3K/Akt signaling pathway. Thus, we demonstrate for the first time that LWD has a neuroprotective effect on APP/PS1 mice and provide theoretical foundation for the development of a new clinical treatment for AD.

Identification of a lncRNA/circRNA-miRNA-mRNA ceRNA Network in Alzheimer's Disease.

Alzheimer's disease (AD) occurs in the elderly and pre-elderly, characterized by decline of memory, cognitive dysfunction, impairment of learning capacity, and motor dysfunction. Recently a competitive endogenous RNA (ceRNA) network has been found to be related to AD progression, but there is still little understanding of the ceRNA regulatory network in AD. This study aims to explore the important regulatory mechanisms of ceRNA regulatory networks containing long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in AD. Data from the gene expression omnibus (GEO) database were used for the analysis. To study enrichment function for the upregulated and downregulated mRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Metascape database, respectively. Based on the STRING database and Cytoscape software 3.9.1, a protein-protein interaction (PPI) network was constructed. The hub genes in this network were identified utilizing the CytoHubba plugin in Cytoscape. The TargetScan, miRWalk, and miRDB were selected to calculate the regulatory interaction between miRNAs and the hub genes. LncRNAs were predicted using RNA22. Additionally, circRNA prediction was executed using the circBank database. 711 downregulated and 670 upregulated overlapping mRNAs were identified between AD and control samples. 32 downregulated and 340 upregulated miRNAs were obtained from AD samples compared with control samples. 78 upregulated and 205 downregulated circRNAs were screened. 275 upregulated lncRNAs and 209 downregulated lncRNAs were found between AD samples and control samples. The PPI network constructed consists of 1016 nodes and 13,946 edges. Ten hub genes were selected to identify target miRNAs and ceRNAs. On the basis of the ceRNA hypothesis, a circRNA/lncRNA-miRNA-mRNA network was established. It included five lncRNAs (TRHDE-AS1, SNHG10, OIP5-AS, LINC00926 and LINC00662), 26 circRNAs, five miRNAs (hsa-miR-3158-3p, hsa-miR-4435, hsa-let-7d-3p, hsa-miR-330-5p and hsa-miR-3605-3p), and ten mRNAs (RPL11, RPL34, RPL21, RPL22, RPL6, RPL32, RPL24, RPL35, RPL31, and RPL35A). RPL35 and RPL35A were found to be significantly associated with AD pathology in tau and Aβ line AD models by the AlzData database. The study discovered the significance of several lncRNA-miRNA-mRNA axes and circRNA-miRNA-mRNA axes that included RPL35A and RPL35. ceRNAs were found to be important regulators in the development of AD and provide potential biological therapy targets for AD management.

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice.

Orexin and its receptors are closely related to the pathogenesis of Alzheimer's disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD.

Advances in targeted tracking and detection of soluble amyloid-β aggregates as a biomarker of Alzheimer's disease

Misfolding and aggregation of amyloid-β (Aβ) peptides are key hallmarks of Alzheimer's disease (AD). With accumulating evidence suggesting that different Aβ species have varied neurotoxicity and implications in AD development, the discovery of affinity ligands and analytical approaches to selective distinguish, detect, and monitor Aβ becomes an active research area. Remarkable advances have been achieved, which not only promote our understanding of the biophysical chemistry of the protein aggregation during neurodegeneration, but also provide promising tools for early detection of the disease. In view of this, we summarize the recent progress in selective and sensitive approaches for tracking and detection of Aβ species. Specific attentions are given to soluble Aβ oligomers, due to their crucial roles in AD development and occurrence at early stages. The design principle, performance of targeting units, and their cooperative effects with signal reporters for Aβ analysis are discussed. The applications of the novel targeting probes and sensing systems for dynamic monitoring oligomerization, measuring Aβ in biosamples and in vivo imaging in brain are summarized. Finally, the perspective and challenges are discussed regarding the future development of Aβ-targeting analytical tools to explore the unknown field to contribute to the early diagnosis and treatment of AD.

Oral Microbiome and Alzheimer's Disease.

The accumulation of amyloid-beta plaques in the brain is a central pathological feature of Alzheimer's disease. It is believed that amyloid responses may be a result of the host immune response to pathogens in both the central nervous system and peripheral systems. Oral microbial dysbiosis is a chronic condition affecting more than 50% of older adults. Recent studies have linked oral microbial dysbiosis to a higher brain Aβ load and the development of Alzheimer's disease in humans. Moreover, the presence of an oral-derived and predominant microbiome has been identified in the brains of patients with Alzheimer's disease and other neurodegenerative diseases. Therefore, in this opinion article, we aim to provide a summary of studies on oral microbiomes that may contribute to the pathogenesis of the central nervous system in Alzheimer's disease.

Cognitive Dysfunction and Affective Mood Disorder Screening in Patients With Chronic Inflammatory Bowel Disease: Protocol for a Prospective Case-Control Study.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) might be more frequent in patients with inflammatory bowel disease (IBD), but the relationship between these 2 entities is yet to be entirely established. Certain blood biomarkers (eg, serum amyloid A [SAA] and serum homocysteine [Hcy], which increase in IBD and MCI; brain-derived neurotrophic factor [BDNF], which decreases in MCI and AD but is not clearly modified in IBD; and S100 calcium-binding protein B [S100B], which increases in the blood-brain barrier and neuronal lesions) might predict the stage of MCI or dementia or progression to a further state. The gut-brain axis (GBA) might be the key to the development of MCI in patients with IBD, along with systemic inflammation and the possible and unknown adverse effects of disease-modifying medication. The aim of this study is to investigate whether GBA interactions play a role in MCI development in patients with IBD. A case-control study will be conducted on at least 100 patients diagnosed with IBD, matched with 100 healthy individual controls. The matching will include sex, age, and education. Patients will be fully examined, and a full interview and a neurological and cognitive examination will be performed. The primary clinical outcomes will be cognitive test scores (Montreal Cognitive Assessment, Trail Making Test, Digit Symbol Substitution Test, forward and backward digit span testing). Depression, stress, and anxiety screening will also be performed. Blood samples from all participants will be collected, and aliquots will be immediately stored in a biobank. Primary laboratory outcomes will include serum levels of presumed cognitive dysfunction blood biomarkers SAA, Hcy, S100B, and BDNF. Follow-up will be performed at 12, 24, 36, and 48 months. Data collection started in December 2021 and is ongoing. So far, 53 patients with IBD have been recruited and 50 HC matched. Data collection should end in January 2030. Intermediary analysis will be performed in April 2024. We expect patients with IBD to have lower scores on cognitive testing and a positive correlation between disease length and cognitive impairment level. In addition, the levels of stress, anxiety, and depression should be higher in the IBD group. The serum levels of the 4 biomarkers could correlate or anticorrelate with cognitive scores and serve as predictive factors for MCI or dementia development. A higher level of education, a younger age, the absence of malabsorption, and good disease control might serve as protectors against MCI. GBA interactions, along with systemic inflammation and the adverse effects of medication, might be a cause of MCI and AD development in patients with IBD. Serum biomarkers could prove cheap and useful predictors of MCI development. ClinicalTrials.gov NCT05760729; https://clinicaltrials.gov/study/NCT05760729. DERR1-10.2196/50546.

Bilberry anthocyanins attenuate mitochondrial dysfunction via β-catenin/TCF pathway in Alzheimer’s disease

Alzheimer’s disease (AD) is a common form of neurodegeneration. In this study, we investigated the modulating effect of bilberry anthocyanins (BAs) on AD-like pathology in the APP/PSEN1 transgenic mouse and then explored the underlying mechanisms using the HT22 cells. We found that BAs significantly reduced the amyloid plaque load and the levels of β-amyloid 1–42 (Aβ42) in the brain and serum of APP/PSEN1 mice. Furthermore, BAs improved mitochondrial morphology and reduced brain NO and ROS levels in the APP/PSEN1 mice. Additional experiments using immortalized HT22 cells showed that BAs protected against Aβ42-induced cytotoxicity by reducing ROS levels and restoring mitochondrial homeostasis, and these effects were partly mediated by upregulation of the mitochondrial homeostasis-related protein Mfn2 via promoting the interaction between β-catenin and TCF7 in nuclear. Together, the results show that BAs have a protective effect against the development of AD, partly through restoration of mitochondrial homeostasis in a β-catenin/TCF-dependent manner.

Apolipoprotein E genotype-dependent accumulation of amyloid β in APP-knock-in mouse model of Alzheimer's disease

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid β (Aβ) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aβ without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aβ pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aβ in vivo, which may not be addressed appropriately by using other transgenic mouse models.

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease.

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood-brain barrier to reach the target areas in the brain or to regulate the function of the blood-brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood-brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Spinosin protects Neuro-2a/APP695 cells from oxidative stress damage by inactivating p38.

To explore the protective mechanism of spinosin (SPI) on Alzheimer's disease (AD) model cells, Neuro-2a/APP695 (N2a/APP695), against HO-induced oxidative stress damage, to reflect the influence of oxidative stress on the development of AD, and to provide a valuable basis for the research and development of therapeutic drug for AD. N2a/APP695 cells were exposed to HO and then treated with spinosin. Firstly, the secretion level of amyloid β (Aβ) and the production of malondialdehyde (MDA) and lactate dehydrogenase (LDH) were detected by enzyme linked immunosorbent assay kits. Secondly, the oligomerization degree of Aβ was performed by Thioflavin T staining. Thirdly, the expression levels of p-Tau (Ser199/202/396), synaptophysin (SYP), postsynaptic density protein 95 (PSD95), and mitogen-activated protein kinase (MAPK) family-related proteins were detected by Western blot analysis. In addition, FITC-labeled phalloidin was used in cytoskeleton staining to reflect synaptic function. This study showed that HO stimulated N2a/APP695 cells to produce excessive MDA and LDH and secrete a large amount of Aβ, promoted the aggregation of Aβ, induced Tau protein hyperphosphorylation, and led to synaptic dysfunction. Spinosin reversed these changes caused by HO by inactivating p38, which was verified by treatment with the p38 inhibitor BIRB796. Spinosin protects N2a/APP695 cells from oxidative stress damage caused by HO through inactivating p38.

Association of Autoimmune Disorders and Disease-modifying Antirheumatic Drugs: (DMARDs) with the Risk of Alzheimer's and/or Dementia: A Population Study Using Medicare Beneficiary Data.

Alzheimer's disease (AD) and/or dementia is a prevalent neurocognitive disorder primarily affecting individuals over the age of 65. Identifying specific causes of AD and/or dementia can be challenging, with emerging evidence suggesting a potential association with autoimmune inflammatory conditions such as rheumatoid arthritis (RA). This study aimed to assess the prevalence rate of AD and/or dementia among Medicare beneficiaries reporting an autoimmune disorder. Additionally, this study sought to identify the comparative prevalence of AD and/or dementia in patients with an autoimmune disorder who were using disease-modifying antirheumatic drugs (DMARDs) compared to those not using DMARDs. Cross-sectional secondary data analyses were conducted on Medicare Current Beneficiary Survey (MCBS) data from 2017 and 2018. The MCBS data consists of a nationally representative sample of the Medicare population, a population that is largely 65 and older, and provides de-identified patient information. Patients from this dataset with a self-reported autoimmune disorder were included in the analyses. Descriptive analyses were conducted on demographic variables, chronic conditions, and medication use. The prevalence of AD and/or dementia was compared between patients with and without an autoimmune disorder. A backward stepwise selection regression was used to identify the risk factors associated with the prevalence of AD and/or dementia. The study included 18,929 Medicare beneficiaries, with 4,405 identified as having one autoimmune disorder. The prevalence of AD and/or dementia was significantly higher in patients with an autoimmune disorder. The multivariate regression showed that RA was significantly associated with a higher risk of AD and/or dementia. Other demographic factors, including advanced age, African-American or Hispanic ethnicity, low body mass index, and chronic conditions of ischemic heart disease, history of myocardial infarction, history of stroke, depression, mental health disorder(s), and traumatic brain injury also showed statistically significant associations with AD and/or dementia. Patients using DMARDs demonstrated a reduced likelihood of having AD and/or dementia, compared to patients not using DMARDs. This study provides evidence of an association between RA and increased risk of AD and/or dementia. The findings suggest that DMARD use may have a protective effect against the development of AD and/or dementia in patients with an autoimmune disorder.

Glycogen Synthase Kinase-3β, NLRP3 Inflammasome, and Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3β (GSK-3β) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1β release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3β-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3β, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3β and the NLRP3 inflammasome in AD as well as their relationship and interaction.

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy.

Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been conducted or are underway on AD, there are still no effective drugs to reverse the pathological features and clinical manifestations of AD. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. As a classical mechanistic target of rapamycin (mTOR) inhibitor, rapamycin has been shown to be beneficial in a variety of AD mouse and cells models, both before the onset of disease symptoms and the early stage of disease. Although many basic studies have demonstrated the therapeutic effects of rapamycin in AD, many questions and controversies remain. This may be due to the variability of experimental models, different modes of administration, dose, timing, frequency, and the availability of drug-targeting vehicles. Rapamycin may delay the development of AD by reducing β-amyloid (Aβ) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in APOE ε4 gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer's disease.

An effective feature selection using improved marine predators algorithm for Alzheimer’s disease classification

<span lang="EN-US">Alzheimer’s disease (AD) is an irremediable neurodegenerative illness developed by the fast deterioration of brain cells. AD is mostly common in elder people and it extremely disturbs the physical and mental health of patients, therefore early detection is essential to prevent AD development. However, the precise detection of AD and mild cognitive impairment (MCI) is difficult during classification. In this paper, the Residual network i.e., ResNet-18 is used for extracting the features, and the proposed improved marine predators algorithm (IMPA) is developed for choosing the optimum features to perform an effective classification of AD. The multi-verse optimizer (MVO) used in the IMPA helps to balance exploration and exploitation, which leads to the selection of optimal relevant features. Further, the classification of AD is accomplished using the multiclass support vector machine (MSVM). Open access series of imaging studies-1 (OASIS-1) and Alzheimer disease neuroimaging initiative (ADNI) datasets are used to evaluate the IMPA-MSVM method. The performance of the IMPA-MSVM method is analyzed using accuracy, sensitivity, specificity, positive predictive value (PPV) and matthews correlation coefficient (MCC). The existing methods such as the <a name="_Hlk134426295"></a>deep learning-based segmenting method using SegNet (DLSS), mish activation function (MAF) with spatial transformer network (STN) and BrainNet2D are used to evaluate the IMPA-MSVM method. The accuracy of IMPA-MSVM for the ADNI dataset is 98.43% which is more when compared to the DLSS and MAF-STN.</span>

Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore

Mitochondrial dysfunction is a significant factor in the development of Alzheimer's disease (AD). Previous studies have demonstrated that the expression of tau cleaved at Asp421 by caspase-3 leads to mitochondrial abnormalities and bioenergetic impairment. However, the underlying mechanism behind these alterations and their impact on neuronal function remains unknown. To investigate the mechanism behind mitochondrial dysfunction caused by this tau form, we used transient transfection and pharmacological approaches in immortalized cortical neurons and mouse primary hippocampal neurons. We assessed mitochondrial morphology and bioenergetics function after expression of full-length tau and caspase-3-cleaved tau. We also evaluated the mitochondrial permeability transition pore (mPTP) opening and its conformation as a possible mechanism to explain mitochondrial impairment induced by caspase-3 cleaved tau. Our studies showed that pharmacological inhibition of mPTP by cyclosporine A (CsA) prevented all mitochondrial length and bioenergetics abnormalities in neuronal cells expressing caspase-3 cleaved tau. Neuronal cells expressing caspase-3-cleaved tau showed sustained mPTP opening which is mostly dependent on cyclophilin D (CypD) protein expression. Moreover, the impairment of mitochondrial length and bioenergetics induced by caspase-3-cleaved tau were prevented in hippocampal neurons obtained from CypD knock-out mice. Interestingly, previous studies using these mice showed a prevention of mPTP opening and a reduction of mitochondrial failure and neurodegeneration induced by AD. Therefore, our findings showed that caspase-3-cleaved tau negatively impacts mitochondrial bioenergetics through mPTP activation, highlighting the importance of this channel and its regulatory protein, CypD, in the neuronal damage induced by tau pathology in AD.