Etiology Of AD Research Articles

Mild atopic dermatitis is characterized by increase in non-staphylococcus pathobionts and loss of specific species

Atopic dermatitis is the most common inflammatory skin condition with a severe negative impact on patients’ quality of life. The etiology of AD is complex and depends on age, genetics, the immune system, environmental factors, and the skin microbiome, with a key role for pathogenic Staphylococcus aureus in the development of severe AD. However, the composition of the skin microbiome in mild AD is understudied. Here, using metagenomic shallow shotgun sequencing, we showed that mild AD lesions did not show a significant difference in the diversity of the skin microbiome compared to samples from non-AD patients and that the relative abundance of S. aureus did not differ in these mild AD lesions. However, when we assessed other taxa, Mycobacterium ostraviense, Pedobacter panaciterrae_A and four Streptomyces species were identified with higher abundances in mild AD lesions and species of 15 genera were decreased in abundance. The highest fold decreases were observed for Paracoccus marcusii, Microbacterium lacticum, Micrococcus luteus, and Moraxella sp002478835. These microbiome compositional insights are a first step towards novel microbiome-based diagnostics and therapeutics for early intervention at the stage of mild AD and provide a path forward for the functional study of species involved in this often-overlooked patient population.

Florbetapir PET-assessed demyelination is associated with faster tau accumulation in an APOE ε4-dependent manner.

The main objectives were to test whether (1) a decrease in myelin is associated with enhanced rate of fibrillar tau accumulation and cognitive decline in Alzheimer's disease, and (2) whether apolipoprotein E (APOE) ε4 genotype is associated with worse myelin decrease and thus tau accumulation. To address our objectives, we repurposed florbetapir-PET as a marker of myelin in the white matter (WM) based on previous validation studies showing that beta-amyloid (Aβ) PET tracers bind to WM myelin. We assessed 43 Aβ-biomarker negative (Aβ-) cognitively normal participants and 108 Aβ+ participants within the AD spectrum with florbetapir-PET at baseline and longitudinal flortaucipir-PET as a measure of fibrillar tau (tau-PET) over ~ 2 years. In linear regression analyses, we tested florbetapir-PET in the whole WM and major fiber tracts as predictors of tau-PET accumulation in a priori defined regions of interest (ROIs) and fiber-tract projection areas. In mediation analyses we tested whether tau-PET accumulation mediates the effect of florbetapir-PET in the whole WM on cognition. Finally, we assessed the role of myelin alteration on the association between APOE and tau-PET accumulation. Lower florbetapir-PET in the whole WM or at a given fiber tract was predictive of faster tau-PET accumulation in Braak stages or the connected grey matter areas in Aβ+ participants. Faster tau-PET accumulation in higher cortical brain areas mediated the association between a decrease in florbetapir-PET in the WM and a faster rate of decline in global cognition and episodic memory. APOE ε4 genotype was associated with a worse decrease in the whole WM florbetapir-PET and thus enhanced tau-PET accumulation. Myelin alterations are associated in an APOE ε4 dependent manner with faster tau progression and cognitive decline, and may therefore play a role in the etiology of AD.

Microglia transcriptional heterogeneity across human and experimental models

AbstractBackgroundThe molecular data from multiple brain regions, cohorts, experimental models are seldom integrated comprehensively, although it provides a unique opportunity to study the cellular heterogeneity and molecular changes across AD etiology and progression. We have developed a new reference model to bridge across datasets.MethodWe leveraged single‐nuclei transcriptomic profiles (snRNA‐seq) of human microglia (parietal cortex from 67 donors from the Knight ADRC and DIAN brain banks; N = 15,726; Dataset1) [1], iPSC‐MLC CRISPRi/a‐based genetic screens in human iPSC‐derived microglia (N = 15,350; Dataset2) [2], and WT and R47H TREM2 xenografted microglia (xMGs), isolated from chimeric AD mice (N = 25,407; Dataset3) [3] to build a comprehensive atlas of microglia heterogeneity, that captures transcriptional states fairly well represented in each dataset. We employed Seurat v4 [4] to integrate the data, and scArches [5] to build classifiers.ResultWe identified homeostatic, activated, interferon (IFN), and IL1B clusters across datasets present in all data we had integrated. In addition, we identified MHCII. We observed that some of the clusters of original states were combined into single clusters. For example, CXCL10‐IFN and INF. We also observed that the integrated data shows a more distinctive expression profile of Type I+II IFN. Furthermore, we build a multiclassifier to label novel microglia generated from hundreds of samples, and data from various experimental models. The cross‐validation analyses indicate that the overall accuracy of the classifier (scArchers) is 0.85 (Fig. 1), although it changes for the distinct datasets [5]. For human microglia in Dataset1 the accuracy was 0.79, while for iPSC‐MLC was 0.73 and 0.96 for Dataset 3. Our results indicate that this multi‐model reference can capture subtle differences better that study‐centric analyses of the data.ConclusionWe are repurposing microglia transcriptomic single‐cell data to build a cross‐species and experimental iPSC‐MLC to bridge across cohorts, species, and experiments. Our results, indicate that this new resource allows to simultaneously interrogate gene expression across different experiments and transcriptional states, and providing the foundation to integrate additional single‐cell molecular data from model organism, ATAC‐seq, and spatially resolved transcriptomics.

Neural responses to peripheral infection in Alzheimer’s disease model mice

AbstractBackgroundClinical and animal studies have suggested that peripheral inflammation affects the central nervous system (CNS) and may be a major factor in the pathophysiology of neurodegenerative diseases like AD. Furthermore, a variety of signaling factors originating in the periphery, such as inflammatory mediators, have been associated with the regulation of brain barrier functions. Here, we hypothesized that the presence of peripheral inflammation dysregulates brain barriers’ integrity and induces neuroinflammation with consequences on amyloid pathology.MethodIn this study, we employed an AD mouse model nasally infected with Staphylococcus aureus to assess the impact of chronic or acute peripheral inflammation on brain transcriptome and amyloid pathology. We utilized both single cell and Spatial Transcriptomics to better determine transcriptional response to peripheral inflammation.ResultThe chronic exposure increased the diffuse and compact amyloid plaques and blood cytokine levels. Following a short‐term exposure, single‐cell and spatial transcriptomics uncovered cell type‐ and spatial‐specific transcriptional changes indicating a dysregulation of the brain barriers, including the blood‐brain and the blood‐cerebrospinal fluid barriers. Brain macrophages exhibited increased Apoe expression and macrophage‐specific genes were upregulated at ventricular areas of infected mice. In addition, we report an increase of disease associated microglia genes around the Ab plaques, together with disbalances in neuronal expression in response to peripheral inflammation.ConclusionWe observed that low‐grade peripheral infection triggers transcriptional responses linked to brain barriers and brain infiltrated/resident macrophages indicate a fundamental importance of them in the mechanisms linking peripheral inflammation and AD pathogenesis. Finally, we showed that bacterial infection caused molecular changes restricted to specific cell types and/or brain spatial microenvironments, which highlights the relevance of studying brain molecular responses with high resolution in order to have new insights on AD etiology.

Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome

AbstractBackgroundBile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.MethodAbsolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.ResultIn stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.ConclusionLeveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.

Cell‐Based Genetic Subtypes Predict Neuroimaging Biomarkers and Clinical Conversion to Alzheimer’s Disease

AbstractBackgroundThe complex etiology and slow progression of AD have complicated efforts to establish robust patient subtypes resulting in high attrition rates among late‐stage clinical trials. We developed a novel procedure to stratify at risk individuals to develop AD using network‐based polygenic risk scores from brain cell‐type specific transcriptome signatures.MethodWe previously computed cell‐based polygenic risk scores (cbPRSs) in the Alzheimer’s Disease Neuroimaging Initiative (Sahelijo et al. 2022). Recently, we computed cbPRSs in 8,481 Framingham Heart Study (FHS) participants using the same genetic markers used in ADNI. We defined low‐ and high‐risk genetic subtypes using the first and the fourth quartiles of the cbPRS distributions, respectively. We conducted association tests with domain specific cognitive tests and neuroimaging biomarkers using subtype risk status as a binary outcome in cognitively normal (CN), mild cognitive impairment (MCI), AD, and all subjects from ADNI. We compared conversion rates from CN and MCI to AD between subtypes using a Cox proportional hazard regression in ADNI and FHS. Using brain‐wide gray matter volume maps with voxel‐based morphometry we compared brain atrophy patterns between subtypes in ADNI corrected for multiple comparisons using Standard FDR at q = 0.05.ResultGenetic subtypes for astrocytes (Ast‐M2) and oligodendrocytes (Oli‐M45) showed significant association with memory and executive function impairment, decreased hippocampal volume, increased amyloid deposition, and decreased glucose metabolism using all subjects from ADNI (P<1.39E‐3). These associations for memory impairment, global amyloid deposition, and decreased glucose metabolism remained significant only in MCI subjects (best P<7.23E‐09). Conversion rates for Ast‐M2 and Oli‐M45 genetic subtypes were significantly different in both ADNI (P<8.67E‐5) and FHS (P<3.90E‐9). These differential conversion rates for Ast‐M2 and Oli‐M45 in FHS were not fully explained by presence of APOE ɛ4 allele (P<0.05 in ɛ4 non‐carriers). Voxel‐wise whole brain analysis identified significant atrophy in bilateral hippocampi, entorhinal cortex, and amygdala for Ast‐M2 (P = 0.0007) and Oli‐M45 (P = 0.001).ConclusionWe demonstrate that polygenic risk scores informed by cell type specific brain transcriptomic networks can stratify at risk subjects with AD related changes in imaging biomarkers and higher chance of progression to AD. These findings provide insight into early detection of cell‐type specific at‐risk individuals for AD.

Analogues Rescues Tau Pathologies and Memory Deficits Inhibiting GSK‐3 Signaling using Scaffold morphing and in silico approaches

AbstractBackgroundAlzheimer’s disease (AD is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid‐beta (Aβ) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has propensity for microtubules, which elevates the instability and tau‐protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK‐3 and is an emerging hypothesis for AD. As a result, attempts are made to conduct investigations and further advancements on new analogues capable of inhibiting the GSK‐3 protein, which are currently in the clinical trials.MethodIn this analysis, we have evaluated certain GSK‐3 inhibitor variants utilizing scaffolding and framework devise technique with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking).ResultThe structure‐based designed analogues interacted effectively with the active amino acids of GSK‐3β target protein. The in silico pharmacokinetic studies revealed their drug‐like properties.ConclusionThe analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK ‐ 3 inhibitors.

Elucidating APOE4‐dependent cholesterol dysregulation in endolysosomes related to Alzheimer’s disease biology

AbstractBackgroundAberrant cholesterol processing may be the missing link in the biology of AD, and in our understanding of AD etiology. APOE4 is a major genetic risk factor for AD, and a key player in cholesterol metabolism in the brain. Previous research from our group has shown that APOE4 is related to increased lysosomal cholesterol accumulation in human iPSC‐astrocytes, and altered endolysosomal morphology has been observed in the entorhinal cortex (EC) of aged APOE4 mice. However, it is unclear how endolysosomal cholesterol mistrafficking changes with age.MethodTherefore, we studied endolysosomal cholesterol accumulation in middle (15‐16month) and old age (25‐26month) old mice, enabling us to study these processes already in mid‐life. We used brain sections of humanized APOE mice, looking at different brain regions to study regional vulnerability and temporal progression. Cholesterol was labeled using the novel and highly specific D4H probe, enabling its quantification within the endolysosomal system using immunohistochemistry. Cholesterol and endolysosomal markers were quantified and colocalized using Cellprofiler.ResultOlder APOE4 mice showed an increase of total cholesterol in their brain, and specifically an increase of lysosomal cholesterol. Middle aged mice did not show a difference in total cholesterol, however, there was a specific decrease in early endosomal (EE) and late endosomal (LE) cholesterol only in the entorhinal cortex (EC) of female APOE3 mice, while lysosomal cholesterol was increased in this group (APOE4 and APOE2 showed similar levels). The EE and LE cholesterol differences were specific to neurons, but not the lysosomal cholesterol increase, indicating that non‐neuronal cells play a role. Another striking finding was the increase of neuronal EE cholesterol in the EC of middle aged APOE3 male vs female mice, whereas the reverse was seen in APOE4 brain tissue.ConclusionAltogether these results indicate that endolysosomal cholesterol is a dynamic process throughout aging, which may play and active role in AD biology. There is a noticeable shift from EE and EL cholesterol changes in midlife, to lysosomal cholesterol accumulation in older age, which are APOE‐genotype dependent. Notably, the EC specifically of female mice show the most variable endolysosomal cholesterol levels, and may be involved in increased vulnerability to pathology.

Economic Burden of Alzheimer’s Disease: A Systematic Review

ObjectivesAlzheimer’s disease (AD) has become one of the most prevalent neurodegenerative disorders among the elderly. The global cost of dementia is expected to reach US $2 trillion in 2030. In this systematic review, existing evidence on the cost of dementia specific to AD is appraised. MethodsA comprehensive search was done on 3 databases, namely PubMed, ScienceDirect, and Web of Science, to identify original cost-of-illness studies that only evaluate the economic burden of AD up to August 2022. The risk of bias in the studies was assessed using Consolidated Health Economic Evaluation Reporting Standards 2022 criteria. Cost articles without specifying etiology of AD or those in non-English were excluded. ResultsTwelve of 5536 studies met the inclusion criteria. The total annual cost of AD per capita ranged from US $468.28 in mild AD to US $171 283.80 in severe AD. The cost of care raised nonlinearly with disease severity. Indirect caregiving cost represented the main contributor to societal cost in community-dwelling patients. When special caregiving accommodation was opted in daily care, it results in cost shifting from indirect cost to direct nonmedical cost. Formal caregiving accommodation caused increase in direct cost up to 67.3% of overall economic burden of the disease. ConclusionsAD exerts a huge economic burden on patients and caregivers. Overall rise of each cost component could be anticipated with disease deterioration. Choice of special caregiving accommodation could reduce caregiver’s productivity loss but increase the direct nonmedical expenditure of the disease from societal perspective.

The role of microbiome-host interactions in the development of Alzheimer´s disease.

Alzheimer`s disease (AD) is the most prevalent cause of dementia. It is often assumed that AD is caused by an aggregation of extracellular beta-amyloid and intracellular tau-protein, supported by a recent study showing reduced brain amyloid levels and reduced cognitive decline under treatment with a beta-amyloid-binding antibody. Confirmation of the importance of amyloid as a therapeutic target notwithstanding, the underlying causes of beta-amyloid aggregation in the human brain, however, remain to be elucidated. Multiple lines of evidence point towards an important role of infectious agents and/or inflammatory conditions in the etiology of AD. Various microorganisms have been detected in the cerebrospinal fluid and brains of AD-patients and have thus been hypothesized to be linked to the development of AD, including Porphyromonas gingivalis (PG) and Spirochaetes. Intriguingly, these microorganisms are also found in the oral cavity under normal physiological conditions, which is often affected by multiple pathologies like caries or tooth loss in AD patients. Oral cavity pathologies are mostly accompanied by a compositional shift in the community of oral microbiota, mainly affecting commensal microorganisms and referred to as 'dysbiosis'. Oral dysbiosis seems to be at least partly mediated by key pathogens such as PG, and it is associated with a pro-inflammatory state that promotes the destruction of connective tissue in the mouth, possibly enabling the translocation of pathogenic microbiota from the oral cavity to the nervous system. It has therefore been hypothesized that dysbiosis of the oral microbiome may contribute to the development of AD. In this review, we discuss the infectious hypothesis of AD in the light of the oral microbiome and microbiome-host interactions, which may contribute to or even cause the development of AD. We discuss technical challenges relating to the detection of microorganisms in relevant body fluids and approaches for avoiding false-positives, and introduce the antibacterial protein lactoferrin as a potential link between the dysbiotic microbiome and the host inflammatory reaction.

Fortasyn Connect Improves Neuropsychiatric Symptoms in Patients with Mild Cognitive Impairment and Dementia: Results from a Retrospective Real-World Study.

Behavioral and psychological symptoms of dementia (BPSD) manifest in the early stages of the disease and impair patients' and caregivers' quality of life. To assess the effectiveness of the nutritional supplement Fortasyn Connect on BPSD for 12 months in people with mild cognitive impairment (MCI) and dementia in clinical practice. Retrospective, national, single-center study of 236 patients (158 MCI and 78 dementia; 55.1% of AD etiology). BPSD were assessed with the Neuropsychiatric Inventory (NPI) at month 3, 6, and 12. Cognition (Mini-Mental State Examination, MMSE), depression (Geriatric Depression Scale, GDS), and everyday functioning (Blessed Dementia Scale, BLS-D; Rapid Disability Rating Scale 2, RDRS2) were also evaluated. Total NPI score, caregiver impact, and symptoms of depression, anxiety, apathy, and irritability improved after 3, 6, and 12 months from Fortasyn Connect initiation (p < 0.001). NPI decreases were more pronounced when baseline NPI score was higher than > 20 points (p < 0.001). The benefit was independent of gender, age, diagnosis, etiology, or concomitant treatment (p < 0.0001), although larger decreases in NPI total score were observed in MCI patients (p < 0.0001). After 12 months, GDS scores decreased (p = 0.042), and MMSE, BLS-D, and RDRS 2 scores remained stable. Fortasyn Connect improved BPSD over at least a year in patients with MCI and dementia. Depression, anxiety, apathy, and irritability were the symptoms that improved the most. The benefit was independent of patients' characteristics and treatment but was greater if prescribed early and when baseline NPI scores were higher.

Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.

The Role of A High-Carbohydrates Diet on Alzheimers Disease

Brain diseases, like majority illnesses, are influenced in some way by nutrition. Alzheimers disease, which is characterized by brain cell deaths and memory loss, is significantly influenced by sugar intake. The frequency, quantity, and type of carbohydrates can influence AD development and outcomes. Whether highly processed or not, carbohydrate-rich foods influence AD. This paper discusses how a high-carbohydrate diet increases the chances of AD development and aggravation. General introduction to carbohydrate diets and the etiology of AD are explained. Subsequently, details on nonmodified and modified AD risk factors are addressed. The present paper moreover examines the imperative relationship between AD and high-carbohydrates diets. Particularly, the paper elucidates how: carbohydrate-rich diets impair cognitive function; how the diet aggravates AD ramifications. Furthermore, the paper evaluates how high-carbohydrates diets: alter AD biomarkers; interact with age to influence AD; and how carbohydrate-rich diets prevent brain cell growth and repair. The report addresses the prevailing therapeutic methods that can be employed to prevent and manage Alzheimers disease. Such interventions include the use of caffeine to significantly less cognitive deterioration in AD patients is addressed. Other interventions addressed regard how ketogenic diets can effectively aid with AD prevention; minimal sugar consumption; and how physical activities can aid AD prevention and management. Besides, AD-derived diseases are also addressed. The paper finds that high-carbohydrate diets should be avoided, and healthier lifestyle practices are integral for AD prevention and management.

Delineating the relationship of Vitamin D binding protein (VDBP) genetic variants in exon 11 with serum Vitamin D levels in Atopic Dermatitis

BackgroundAtopic Dermatitis (AD) is a multifactorial cutaneous disorder with a profound impact on the quality of life of patients. In terms of AD etiology, vitamin D deficiency is gaining relevance owing to its role in skin barrier function and the keratinocyte proliferation process. This study seeks to ascertain the role of Vitamin D Binding Protein (VDBP) genetic variants (rs7041 and rs4588) in determining serum Vitamin D levels in AD patients as well as to investigate their role in AD susceptibility and severity. MethodsAn aggregate of 210 subjects including 100 AD cases and 110 matched controls were genotyped for VDBP SNPs by PCR-RFLP. The severity of AD was evaluated using the SCORAD index. Total IgE and Vitamin D levels were estimated by ELISA and chemiluminescence, respectively. ResultsThe CC genotype of rs4588 was linked to higher Vitamin D levels whereas the AA genotype was linked to lower levels of Vitamin D (p = 0.02). Besides, mean serum Vitamin D levels were less in females (p = 0.02), older patients (p = 0.01), and with a severe form of the disease (p = 0.01). Overall, the genotypic and allelic frequency of both SNPs showed no significant difference among cases and controls. ConclusionThis study reveals that VDBP SNP rs4588 could be a possible modulator of serum Vitamin D levels and hence bears important clinical implications in AD.

Multifactorial glial responses and their contributions to Alzheimer's disease continuum

AbstractAlzheimer's disease (AD) is the most common neurocognitive disorder. Various factors are intricately intertwined before clinical symptoms appear, although both amyloid‐β peptide deposition and neurofibrillary tangle formation (i.e. pathological hallmarks of the AD brain) are established. Among such factors, glial responses have been increasingly recognized as important roles in the progression of these pathologies and viewed as one component of the AD continuum. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain to be elucidated. Recent studies showed that peripheral immunity, gut microbiota or environmental factors influence brain pathophysiologies through communication with glial cells in the brain. This disease complexity makes understanding AD etiology difficult and hinders the development of effective therapeutic strategies to tackle this disease. Conversely, aged patients often suffer from multiple – not a single – diseases as multimorbidity, and AD pathogenesis might be related to pathologies caused by other diseases. Hence, investigating AD as a systemic disease has become critical for identifying therapeutic interventions. This review aimed to summarize current knowledge on AD research and share perspectives for understanding glial functions regarding AD pathophysiology.

Human cytomegalovirus-encoded microRNAs expression profile in plasma of patients with aortic dissection

BackgroundAortic dissection (AD) is a rare disease with high mortality for which no effective diagnostic biomarkers are available. Human cytomegalovirus (HCMV) infection is an important cause of the occurrence and progression of many diseases, but the relationship between HCMV infection and AD is not clear.MethodsIn this study, we first used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to determine the expression profile of 25 HCMV-encoded microRNAs (HCMV miRNAs) in the plasma within a training set consisting of 20 AD patients and 20 healthy controls. Then, abnormal expressed HCMV miRNAs were verified in a validation set of 12 AD patients and 12 healthy controls. In addition, HCMV infection was detected in the third cohort consisting of 20 AD patients and 20 healthy controls.ResultsThe 95% quantile of the expression levels of HCMV miRNAs in the training set was used as the threshold for distinction between AD patients and healthy controls. The proportion of individuals with high level of five types of HCMV miRNAs was significantly different between AD patients and healthy controls. In the validation set, only the proportion of individuals with high levels of hcmv-miR-UL112-5p and hcmv-miR-UL22A-5p, two of the five HCMV miRNAs obtained in the preliminary screening, showed significant difference between AD patients and healthy controls. In the third cohort, there was no significant difference in HCMV DNA levels and anti-HCMV IgG concentrations between AD patients and healthy controls.ConclusionsThe HCMV miRNAs levels in plasma differed in AD patients and healthy controls. This finding may contribute to a further understanding of the relationship between HCMV infection and AD and are worthy of future research on the diagnosis and etiology of AD.

Pyroglutamate-modified amyloid β(3-42) monomer has more β-sheet content than the amyloid β(1-42) monomer.

The aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer's disease. This peptide can aggregate into oligomers, proto-fibrils and mature fibrils, which eventually assemble into amyloid plaques in vivo. Several post-translational modifications lead to the presence of different forms of the Aβ peptide in the amyloid plaques with different biophysical and biochemical properties. While the canonical forms Aβ(1-40) and Aβ(1-42) have been found to be the major components of amyloid plaques, N-terminally pyroglutamate-modified variants, specifically pE-Aβ(3-42), amount to a significant fraction of the total Aβ plaque content of AD brains. With increased hydrophobicity, these variants display a more pronounced aggregation behaviour in vitro which, together with their higher stability against degradation in vivo is thought to make them crucial molecular players in the aetiology of AD. The peptide monomers are the smallest assembly units, and play an important role in most of the individual molecular processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. Understanding the monomeric conformational ensembles of the isoforms is important in unraveling observed differences in their bio-physico-chemical properties. Here we use enhanced and extensive molecular dynamics simulations to study the structural flexibility of the N-terminally truncated Pyroglutamate modified isomer of Aβ, pE-Aβ(3-42) monomer, and compared it with simulations of the Aβ(1-42) peptide monomer under the same conditions. We find significant differences, especially in the secondary structure and hydrophobic exposure, which might be responsible for their different behaviour in biophysical experiments.

Understanding the Intricate Role of Exosomes in Pathogenesis of Alzheimer's Disease.

Alzheimer's disease causes loss of memory and deterioration of mental abilities is utmost predominant neurodegenerative disease accounting 70-80% cases of dementia. The appearance of plaques of amyloid-β and neurofibrillary tangles in the brain post-mortems of Alzheimer's patients established them as key participants in the etiology of Alzheimer's disease. Exosomes exist as extracellular vesicles ofnano-size which are present throughout the body. Exosomes are known to spread toxic hyperphosphorylated tau and amyloid-β between the cells and are linked to the loss of neurons by inducing apoptosis. Exosomes have progressed from cell trashcans to multifunctional organelles which are involved in various functions like internalisation and transmission of macromolecules such as lipids, proteins, and nucleic acids. This review covers current findings on relationship of exosomes in biogenesis and angiogenesis of Alzheimer's disease and functions of exosomes in the etiology of AD. Furthermore, the roles of exosomes in development, diagnosis, treatment, and its importance as therapeutic targets and biomarkers for Alzheimer's disease have also been highlighted.

Translational potential of JAX humanized APOE mice: Metabolism and body composition in very old mice

AbstractBackgroundApolipoprotein (APOE) is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Clinically, LOAD exhibits strong sex effects with females being twice at the risk of developing AD than males. Models exhibiting strong AD etiology are used in preclinical settings, however lack of translatability necessitates model development with a reverse translational approach. This study explores metabolic hallmarks of LOAD assessing the clinical translatability of the JAX humanized APOE (hAPOE) mouse model.MethodhAPOE mice (M/F, n = 65, mean age = 23.35 +/‐ 0.90 months) with e3/3, e3/4 or e4/4 genotype underwent a metabolic and body composition screening assay including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18F‐FDG‐PET brain imaging, prior to being sacrificed. Blood plasma was analyzed for triglyceride levels. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum. All data were analyzed with genotype x sex analysis of variance. P ≤ 0.05 was considered statistically significant and post‐hoc pairwise analyses were conducted for interaction effects with p ≤ 0.1 (FKB, adipose index) for future study planning.ResultFemales had significantly lower lean mass (p &lt; 0.0001) and FBG (p=0.05), with a trend toward lower glucose uptake on FDG‐PET compared to males (p=0.072). Post‐hoc interaction analyses of FKB (interaction p=0.105) demonstrated lower ketone body levels in male e4/4s compared to female e4/4s (uncorrected p=0.0685) and male e3/4s (p=0.034). Post‐hoc interaction analyses of adipose index (interaction p=0.093) demonstrated greater adiposity in female e4/4s compared to male e4/4s (uncorrected p=0.005) and female e3/3s (uncorrected p=0.035). No effects of APOE genotype were observed.ConclusionIn a mouse cohort at a comparable human age of ∼ 70 years, lower lean mass, fasting blood glucose, and glucose uptake in the brain for female mice indicates ongoing bioenergetic deficits and is corroborated by observations within clinical populations. Greater adiposity in female e4/4s suggests that brain bioenergetic demand is not being met through fat reserves. However, the overall lack of genotypic effects suggests this bioenergetic crisis is not driven by hAPOE in this animal model, limiting clinical translatability.NIA R01AG057931; University of Arizona TBIR (NIH S10 OD025016).

Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease

A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.