Development Of Alzheimer's Disease Research Articles

The Kynurenine Pathway, Aryl Hydrocarbon Receptor, and Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by β-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.

Chronic stress induces insulin resistance and enhances cognitive impairment in AD

BackgroundChronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. MethodsMale 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). ResultsFour weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice. ConclusionsChronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions.

Worldwide, around 50 million people live with dementia, and this number is projected to triple by 2050. It has been estimated that 20% of all dementia cases have a predominant cerebrovascular pathology, while perhaps another 20% of vascular diseases contribute to a mixed dementia picture. Therefore, the vascular contribution to dementia affects 20 million people currently and will increase markedly in the next few decades, particularly in lower- and middle-income countries.In this review, we discuss the mechanisms of vascular cognitive impairment (VCI) and review management. VCI refers to the spectrum of cerebrovascular pathologies that contribute to any degree of cognitive impairment, ranging from subjective cognitive decline, to mild cognitive impairment, to dementia. While acute cognitive decline occurring soon after a stroke is the most recognized form of VCI, chronic cerebrovascular disease, in particular cerebral small-vessel disease, can cause insidious cognitive decline in the absence of stroke. Moreover, cerebrovascular disease not only commonly co-occurs with Alzheimer's disease (AD) and increases the probability that AD pathology will result in clinical dementia, but may also contribute etiologically to the development of AD pathologies.Despite its enormous health and economic impact, VCI has been a neglected research area, with few adequately powered trials of therapies, resulting in few proven treatments. Current management of VCI emphasizes prevention and treatment of stroke and vascular risk factors, with most evidence for intensive hypertension control. Reperfusion therapies in acute stroke may attenuate the risk of VCI. Associated behavioral symptoms such as apathy and poststroke emotionalism are common. We also highlight novel treatment strategies that will hopefully lead to new disease course-modifying therapies. Finally, we highlight the importance of including cognitive endpoints in large cardiovascular prevention trials and the need for an increased research focus and funding for this important area.

The ameliorative potential of metformin against aluminum-induced neurotoxicity: Insights from in vitro studies.

Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder, often referred to as type 3 diabetes, due to its strong association with insulin resistance. Chronic exposure to aluminum, a known neurotoxin, has been identified as a significant risk factor in the development and progression of AD. This study explores the potential of metformin, a common anti-diabetic drug, to mitigate aluminum-induced neurotoxicity in an in vitro model of AD. Our findings reveal that metformin significantly reduces oxidative stress markers such as malonaldehyde, carbonyl groups, and reactive oxygen species while enhancing antioxidant defenses. Metformin modulates critical signaling pathways, including glycogen synthase kinase 3 beta (GSK3-β)/RAC-alpha serine/threonine protein kinase (RAC-alpha serine/threonine protein kinase (Akt1)/protein phosphatase 2A (PP2A) and Wnt/β-catenin, decreasing Tau protein levels and promoting neurogenesis. These results suggest that metformin may offer a novel therapeutic approach for AD, particularly in cases where aluminum exposure is a contributing factor.

Gut-Brain Nexus: Mapping Multi-Modal Links to Neurodegeneration at Biobank Scale.

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. Using data from UK Biobank, SAIL Biobank, and FinnGen, we conducted an unbiased, population-scale study to: 1) Investigate how 155 endocrine, nutritional, metabolic, and digestive system disorders are associated with AD and PD risk prior to their diagnosis, considering known genetic influences; 2) Assess plasma biomarkers' specificity for AD or PD in individuals with these conditions; 3) Develop a multi-modal classification model integrating genetics, proteomics, and clinical data relevant to conditions affecting the gut-brain axis. Our findings show that certain disorders elevate AD and PD risk before AD and PD diagnosis including: insulin and non-insulin dependent diabetes mellitus, noninfective gastro-enteritis and colitis, functional intestinal disorders, and bacterial intestinal infections, among others. Polygenic risk scores revealed lower genetic predisposition to AD and PD in individuals with co-occurring disorders in the study categories, underscoring the importance of regulating the gut-brain axis to potentially prevent or delay the onset of neurodegenerative diseases. The proteomic profile of AD/PD cases was influenced by comorbid endocrine, nutritional, metabolic, and digestive systems conditions. Importantly, we developed multi-modal prediction models integrating clinical, genetic, proteomic and demographic data, the combination of which performs better than any single paradigm approach in disease classification. This work aims to illuminate the intricate interplay between various physiological factors involved in the gut-brain axis and the development of AD and PD, providing a multifactorial systemic understanding that goes beyond traditional approaches.

From Viral Infections to Alzheimer's Disease: Unveiling the Mechanistic Links Through Systems Bioinformatics.

Emerging evidence suggests that viral infections may contribute to Alzheimer's disease (AD) onset and/or progression. However, the extent of their involvement and the mechanisms through which specific viruses increase AD susceptibility risk remain elusive. We used an integrative systems bioinformatics approach to identify viral-mediated pathogenic mechanisms, by which Herpes Simplex Virus 1 (HSV-1), Human Cytomegalovirus (HCMV), Epstein-Barr virus (EBV), Kaposi Sarcoma-associated Herpesvirus (KSHV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Influenza A Virus (IAV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could facilitate AD pathogenesis via virus-host protein-protein interactions (PPIs). We also explored potential synergistic pathogenic effects resulting from herpesvirus reactivation (HSV-1, HCMV, and EBV) during acute SARS-CoV-2 infection, potentially increasing AD susceptibility. Herpesviridae members (HSV-1, EBV, KSHV, HCMV) impact AD-related processes like amyloid-β (Aβ) formation, neuronal death, and autophagy. Hepatitis viruses (HBV, HCV) influence processes crucial for cellular homeostasis and dysfunction, they also affect microglia activation via virus-host PPIs. Reactivation of HCMV during SARS-CoV-2 infection could potentially foster a lethal interplay of neurodegeneration, via synergistic pathogenic effects on AD-related processes like response to unfolded protein, regulation of autophagy, response to oxidative stress, and Aβ formation. These findings underscore the complex link between viral infections and AD development. Viruses impact AD-related processes through shared and distinct mechanisms, potentially influencing variations in AD susceptibility.

Recent Advances of Mitochondrial Alterations in Alzheimer's Disease: A Perspective of Mitochondrial Basic Events.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations- bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission- fusion dynamics, mitochondrial degradation, and mitochondrial movement- underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis.

Apolipoprotein E and Alzheimer's Disease in Italian Population: Systematic Review and Meta-Analysis.

Objective: This meta-analysis with a systematic review was undertaken to assess the association between APOE allelic genotypes and the risk of Alzheimer's disease (AD) in the Italian population. Methods: The Web of Science, PubMed, and Scopus databases were searched until 15 November 2023. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using fixed and random effect models, depending on the I2 statistic value. The systematic review and meta-analysis were conducted in agreement with the PRISMA guideline and registered with PROSPERO (CRD42023492580). Results: Our meta-analysis based on 15 studies revealed a higher risk of AD among Italian individuals carrying the APOE ε4 allele (OR = 3.60, 95% CI [2.90-4.47], p < 0.0001). The association of AD genotype APOE ε2ε4 (OR = 1.36, 95% CI [0.76-2.41], p = 0.29) was not statistically significant, while APOE ε3ε4 (OR = 3.43, 95% CI [2.95-3.99], p < 0.0001) has a high risk of AD development; the risk is more notably in the APOE ε4ε4 genotype (OR = 7.08, 95% CI [4.22-11.86], p < 0.0001). The APOE ε2 allele has a protective effect (APOE ε2 (OR = 0.47, 95% CI [0.29-0.74], p = 0.0013)), and similar results were achieved by APOE ε3 (OR = 0.49, 95% CI [0.37-0.65], p < 0.0001). Subgroup analysis of three areas of Italy (southern, northern, and center) revealed that that APOE ε4 allele was a risk factor with a higher OR in northern Italy (OR 4.22; 95% CI [3.46-5.16], p < 0.0001) compared to southern and center Italy (OR 3.02; 95% CI [2.28-4.01], p < 0.0001 and OR 3.97; 95% CI [1.37-11.56], p < 0.0001, respectively). As well, APOE ε4ε4 genotype carriers had a significantly higher OR in northern Italy (OR 9.69; 95% CI [4.94-18.99], p < 0.0001) compared to in southern and center Italy (OR 4.38; 95% CI [1.54-12.47], p < 0.0001 and OR 3.59; 95% CI [0.87-14.86], p < 0.0001, respectively). Conclusions: This systematic review with a meta-analysis of the Italian population on APOE alleles, genotyping, and AD incidence, highlights that individuals harboring APOE ε4 have a higher risk of developing AD compared to those with other alleles. It also supports the protective effect of the APOE ε2 allele against the progress of AD. The qualitative analysis on the complex genetic interactions influencing Alzheimer risk emphasizes the need for further research on genetic and environmental factors for effective prevention strategies.

Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer's Disease Therapeutics.

Therapeutic research and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and neurodegeneration. There is growing interest in drug repositioning and repurposing strategies for FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA drug efavirenz has been investigated as a candidate drug for repurposing as an AD medication. The proposed mechanism of action of efavirenz (at low doses) is the activation of the neuron-specific enzyme CYP46A1 that converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) that is exported to the periphery. Efavirenz at a low dose was found to improve memory deficit in the 5XFAD model of AD that was accompanied by elevated 24-HC and reduction in Aβ; furthermore, efavirenz reduced pTau and excess cholesterol levels in human iPSC-derived Alzheimer's neurons. The low dose of efavirenz used in the AD mouse model to increase 24-HC contrasts with the use of more than 100-fold higher doses of efavirenz for clinical treatment of human immunodeficiency virus (HIV) through inhibition of reverse transcriptase. Low doses of efavirenz may avoid neurotoxic adverse effects that occur at high efavirenz doses used for HIV treatment. This review evaluates the drug properties of efavirenz with respect to its preclinical data on regulating memory deficit, pharmacokinetics, pharmacodynamics, metabolites, and genetic variabilities in drug metabolism as well as its potential adverse effects. These analyses discuss the challenges and questions that should be addressed in future studies to consider the opportunity for low dose efavirenz as a candidate for AD drug development.

Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: Common Molecular Mechanism and Therapeutic Targets.

Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aβ) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3β in AD is intriguing. These proteins' association with T2DM and pancreatic β-cell failure suggests they might be therapeutic targets for both disorders.

Nanoscale Structural Characterization of Amyloid β 1-42 Oligomers and Fibrils Grown in the Presence of Fatty Acids.

Mono- and polyunsaturated fatty acids (FAs) are broadly used as food supplements. However, their effect on the aggregation of amyloidogenic proteins remains unclear. In this study, we investigated the effect of a large number of mono- and polyunsaturated, as well as fully saturated FAs on the aggregation of amyloid β1-42 (Aβ1-42) peptide. A progressive aggregation of this peptide is the expected molecular cause of Alzheimer's disease (AD), one of the most common neurodegenerative pathologies in the world. We found that arachidonic and stearic acids delayed the aggregation of Aβ1-42. Using Nano-Infrared spectroscopy, we found that FAs caused very little if any changes in the secondary structure of Aβ1-42 oligomers and fibrils formed at different stages of protein aggregation. However, the analyzed mono- and polyunsaturated, as well as fully saturated FAs uniquely altered the toxicity of Aβ1-42 fibrils. We found a direct relationship between the degree of FAs unsaturation and toxicity of Aβ1-42 fibrils formed in their presence. Specifically, with an increase in the degree of unsaturation, the toxicity Aβ1-42/FA fibrils increased. These results indicate that fully saturated or monounsaturated FAs could be used to decrease the toxicity of amyloid aggregates and, consequently, decelerate the development of AD.

Identification of Alzheimer’s disease and vascular dementia based on a Deep Forest and near-infrared spectroscopy analysis method

Alzheimer’s disease (AD) and vascular dementia (VaD) typically do not exhibit distinct differences in clinical manifestations and auxiliary examination results, which leads to a high misdiagnosis rate. However, significant differences in treatment approaches and prognosis between these two diseases underscore the critical need for an accurate diagnosis of AD and VaD. In this study, serum samples from 33 patients with AD patients, 37 patients with VaD, and 130 healthy individuals were collected, employing near-infrared aquaphotomics technology in combination with deep learning for differential diagnoses. Through an analysis of water absorption patterns among different diseases via aquaphotomics, the efficacies of traditional machine learning methods (Support Vector Machine and Decision Trees) and deep learning approaches (Deep Forest) in modeling were compared. Ultimately, by leveraging feature extraction techniques in conjunction with deep learning, a differential diagnostic model for AD and VaD was successfully developed. The results revealed that aquaphotomics could identify a certain correlation between the number of hydrogen bonds in water molecules and the development of AD and VaD; the deep learning model was found to be superior to traditional machine learning models, achieving an accuracy of 98.67 %, sensitivity of 97.33 %, and specificity of 100.00 %. The bands identified using the Competitive Adaptive Reweighting Algorithm method, primarily located at approximately 1300–1500 nm, showed a significant correlation with water molecules containing four hydrogen bonds. These results highlighted the potential role of the water molecule hydrogen-bond network in disease development and were consistent with the aquaphotomics analysis results. Therefore, the differential diagnostic model developed by integrating near-infrared spectroscopy and deep learning was proven to be effective and feasible, providing accurate and rapid diagnostic methods for AD and VaD diagnoses.

Cinnamic Acid Derivatives: Recent Discoveries and Development Strategies for Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline and memory impairment. It is characterized by the accumulation of Amyloid-beta (Aβ) plaques, the abnormal phosphorylation of tau protein forming neurofibrillary tangles, and is often accompanied by neuroinflammation and oxidative stress, which contribute to neuronal loss and brain atrophy. At present, clinical anti-AD drugs are mostly single-target, improving the cognitive ability of AD patients, but failing to effectively slow down the progression of AD. Therefore, research on effective multi-target drugs for AD has become an urgent problem to address. The main derivatives of hydroxycinnamic acid, caffeic acid, and ferulic acid, are widely present in nature and have many pharmacological activities, such as antimicrobial, antioxidant, anti-inflammatory, neuroprotective, anti-Aβ deposition, and so on. The occurrence and development of AD are often accompanied by pathologies, such as oxidative stress, neuroinflammation, and Aβ deposition, suggesting that caffeic acid and ferulic acid can be used in the research on anti-AD drugs. Therefore, in this article, we have summarized the multi-target anti-AD derivatives based on caffeic acid and ferulic acid in recent years, and discussed the new design direction of cinnamic acid derivatives as backbone compounds. It is hoped that this review will provide some useful strategies for anti-AD drugs based on cinnamic acid derivatives.

Common molecular and pathophysiological underpinnings of delirium and Alzheimer’s disease: molecular signatures and therapeutic indications

BackgroundDelirium and Alzheimer's disease (AD) are common causes of cognitive dysfunction among older adults. These neurodegenerative diseases share a common and complex relationship, and can occur individually or concurrently, increasing the chance of permanent mental dysfunction. However, the common molecular pathophysiology, key proteomic biomarkers, and functional pathways are largely unknown, whereby delirium is superimposed on AD and dementia.MethodsWe employed an integrated bioinformatics and system biology analysis approach to decipher such common key proteomic signatures, pathophysiological links between delirium and AD by analyzing the gene expression data of AD-affected human brain samples and comparing them with delirium-associated proteins. The present study identified the common drug target hub-proteins examining the protein–protein interaction (PPI) and gene regulatory network analysis. The functional enrichment and pathway analysis was conducted to reveal the common pathophysiological relationship. Finally, the molecular docking and dynamic simulation was used to computationally identify and validate the potential drug target and repurposable drugs for delirium and AD.ResultsWe detected 99 shared differentially expressed genes (sDEGs) associated with AD and delirium. The sDEGs-set enrichment analysis detected the transmission across chemical synapses, neurodegeneration pathways, neuroinflammation and glutamatergic signaling pathway, oxidative stress, and BDNF signaling pathway as the most significant signaling pathways shared by delirium and AD. The disease-sDEGs interaction analysis highlighted the other disease risk factors with delirium and AD development and progression. Among the sDEGs of delirium and AD, the top 10 hub-proteins including ALB, APP, BDNF, CREB1, DLG4, GAD1, GAD2, GFAP, GRIN2B and GRIN2A were found by the PPI network analysis. Based on the maximum molecular docking binding affinities and molecular dynamic simulation (100 ns) results, the ALB and GAD2 were found as prominent drug target proteins when tacrine and donepezil were identified as potential drug candidates for delirium and AD.ConclusionThe study outlined the common key biomolecules and biological pathways shared by delirium and AD. The computationally reported potential drug molecules need a deeper investigation including clinical trials to validate their effectiveness. The outcomes from this study will help to understand the typical pathophysiological relationship between delirium and AD and flag future therapeutic development research for delirium.

Development of Alzheimer's disease and the organic changes involved in the process

Development of Alzheimer's disease and the organic changes involved in the process

Elucidating the Functional Roles of Long Non-Coding RNAs in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by cognitive decline and neuronal loss, representing a most challenging health issue. We present a computational analysis of transcriptomic data of AD tissues vs. healthy controls, focused on the elucidation of functional roles played by long non-coding RNAs (lncRNAs) throughout the AD progression. We first assembled our own lncRNA transcripts from the raw RNA-Seq data generated from 527 samples of the dorsolateral prefrontal cortex, resulting in the identification of 31,574 novel lncRNA genes. Based on co-expression analyses between mRNAs and lncRNAs, a co-expression network was constructed. Maximal subnetworks with dense connections were identified as functional clusters. Pathway enrichment analyses were conducted over mRNAs and lncRNAs in each cluster, which served as the basis for the inference of functional roles played by lncRNAs involved in each of the key steps in an AD development model that we have previously built based on transcriptomic data of protein-encoding genes. Detailed information is presented about the functional roles of lncRNAs in activities related to stress response, reprogrammed metabolism, cell polarity, and development. Our analyses also revealed that lncRNAs have the discerning power to distinguish between AD samples of each stage and healthy controls. This study represents the first of its kind.

Beliefs About the Causes of Alzheimer's Disease Among Latinos in New York City.

Latinos face health disparities in Alzheimer's disease (AD), with high disease prevalence relative to non-Latino whites and barriers to healthcare access. Several studies have found misconceptions about AD among Latinos that were linked to reduced preventative or help-seeking behavior. To improve understanding of illness perceptions among Latinos, we examined beliefs about the causes of AD, one of the five dimensions of illness representations from Leventhal's Self-Regulation Theory, among a sample of N = 216 Latinos. We conducted in-depth, semi-structured interviews with participants aged 40 to 64 (average age 53 years) living in northern Manhattan. Seven distinct causes of AD were identified, though participants demonstrated a general understanding of AD as a multifactorial disease. Genetics was found to be the most endorsed cause of AD, followed by unhealthy lifestyle factors. Most Latinos who believed psychosocial factors played a critical role in AD development were first-generation immigrants. No participants attributed AD to a normal process of aging, and few ascribed the disease to brain damage from stroke or head injuries. Several participants expressed the belief that environmental contaminants can cause AD, which has received little mention in prior studies. Though only a small number thought AD could occur by chance, most participants remained uncertain about the exact causes of the disease and used lay knowledge to explain their beliefs. Our findings help identify areas where educational interventions would be beneficial in improving community knowledge and offer perspectives that can foster cultural competency in healthcare.

Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer's Disease.

Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer's disease following space travel. In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer's disease mouse model. Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiation. The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models.

Cooperative nuclear action of RNA-binding proteins PSF and G3BP2 to sustain neuronal cell viability is decreased in aging and dementia.

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging- and AD-associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA-seq) analysis of human neuronal cells has shown that PSF is responsible for neuron-specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF-mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis demonstrated that the interaction of RBPs with the pre-mRNA of target genes enhanced post-transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non-AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development.

Single-Nucleus Landscape of Glial Cells and Neurons in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a projected significant increase in incidence. Therefore, this study analyzed single-nucleus AD data to provide a theoretical basis for the clinical development and treatment of AD. We downloaded AD-related monocyte data from the Gene Expression Omnibus database, annotated cells, compared cell abundance between groups, and investigated glial and neuronal cell biological processes and pathways through functional enrichment analysis. Furthermore, we constructed a global regulatory network for AD based on cell communication and ecological analyses. Our findings revealed increased abundance of Capping Protein Regulator And Myosin 1 linker 1 (CARMIL1)+ astrocytes (AST), Immunoglobulin Superfamily Member 21 (IGSF21)+ microglia (MIC), SRY-Box Transcription Factor 6 (SOX6)+ inhibitory neurons (InNeu), and laminin alpha-2 chain (LAMA2)+ oligodendrocytes (OLI) cell subgroups in tissues of patients with AD, while prostaglandin D2 synthase (PTGDS)+ AST, Src Family Tyrosine Kinase (FYN)+ MIC, and Proteolipid Protein 1 (PLP1)+ InNeu subgroups specifically decreased. We found that the cell phenotype of patients with AD shifted from a simpler to a more complex state compared to the control group. Cell communication analysis revealed strong communication between MIC and NEU. Furthermore, AST, MIC, NEU, and OLI were involved in oxidative stress- and inflammation-related pathways, potentially contributing to disease development. This study provides a theoretical basis for further exploring the specific mechanisms underlying AD.