Expression Of AD-related Genes Research Articles

Data-driven decomposition and staging of flortaucipir uptake in Alzheimer's disease.

Previous approaches pursuing in vivo staging of tau pathology in Alzheimer's disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. We selected discovery (n=418) and replication (n=132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression.

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

AbstractTargeting the non-nuclear estrogen receptor (ER) signaling has been postulated as novel therapeutic strategy for central nervous system pathologies. Recently, we showed that newly designed PaPE-1 (Pathway Preferential Estrogen-1), which selectively activates ER non-nuclear signaling pathways, elicited neuroprotection in a cellular model of Alzheimer’s disease (AD) when it was applied at the same time as amyloid-β (Aβ). Since delayed treatment reflects clinical settings better than cotreatment does, current basic study proposes a novel therapeutic approach for AD that relies on a posttreatment with PaPE-1. In this study, mouse neuronal cell cultures treated with preaggregated Aβ1-42 (10 µM) showed the presence of extracellular Aβ1-42, confirming the adequacy of the AD model used. We are the first to demonstrate that a 24-h delayed posttreatment with PaPE-1 decreased the degree of Aβ-induced neurodegeneration, restored neurite outgrowth, and inhibited the expression of AD-related genes, i.e., Rbfox, Apoe, Bace2, App, and Ngrn, except for Chat, which was stimulated. In addition, PaPE-1 elicited anti-apoptotic effects by inhibiting Aβ-induced caspase activities as well as attenuating apoptotic chromatin condensation, and in these ways, PaPE-1 prevented neuronal cell death. Posttreatment with PaPE-1 also downregulated the Aβ-affected mRNA expression of apoptosis-specific factors, such as Bax, Gsk3b, Fas, and Fasl, except for Bcl2, which was upregulated by PaPE-1. In parallel, PaPE-1 decreased the protein levels of BAX, FAS, and FASL, which were elevated in response to Aβ. PaPE-1 elicited a decrease in the BAX/BCL2 ratio that corresponds to increased methylation of the Bax gene. However, the PaPE-1-evoked Bcl2 gene hypermethylation suggests other PaPE-1-dependent mechanisms to control Aβ-induced apoptosis.

LncRNA ENST00000440246.1 Promotes Alzheimer's Disease Progression by Targeting PP2A.

Alzheimer's disease (AD) is an extremely prevalent neurodegenerative disease. Long noncoding RNAs (lncRNAs) play pivotal roles in the regulation of AD. However, the function of most lncRNAs in AD remains to be elucidated. In this study, the effects of lncRNA ENST00000440246.1 on the biological characteristics of AD were explored. Differentially expressed lncRNAs in AD were identified through bioinformatics analysis and peripheral blood from thirty AD patients was collected to verify the expression of these lncRNAs by quantitative real-time polymerase chain reaction (RT-qPCR). The correlations between lncRNAs and the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA) were assessed by Pearson's correlation analysis. Immunofluorescence (IF), Cell Counting Kit-8 (CCK-8) and flow cytometry assays were conducted to evaluate the biological effect of ENST00000440246.1 and protein phosphatase 2A (PP2A) in SK-N-SH cells. Gene expression at the protein and mRNA levels was analyzed by Western blotting and RT-qPCR. The interaction between PP2A and ENST00000440246.1 was confirmed by IntaRNA and RNA pulldown assays. ENST00000440246.1 was upregulated and significantly negatively correlated with the MMSE and MoCA scores and the overexpression of ENST00000440246.1 inhibited cell proliferation and facilitated apoptosis and Aβ expression in SK-N-SH cells. Mechanistically, ENST00000440246.1 targeted PP2A and regulated AD-related gene expression. The silencing of ENST00000440246.1 had the opposite effect. Furthermore, PP2A overexpression reversed the influence of ENST00000440246.1 overexpression in SK-N-SH cells. In conclusion, ENST00000440246.1 could promote AD progression by targeting PP2A, which indicates that ENST00000440246.1 has the potential to be a diagnostic target in AD.

Tolfenamic Acid Derivatives: A New Class of Transcriptional Modulators with Potential Therapeutic Applications for Alzheimer's Disease and Related Disorders.

The field of Alzheimer's disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs that interfere with sequence-specific DNA binding at transcription start sites and predominantly modulate the expression of SP1 target genes. More importantly, the proteome of treated cells displayed ~75% of the downregulated products as SP1 targets. Specific levels of SP1-driven genes and AD biomarkers such as amyloid precursor protein (APP) and Tau proteins were also decreased as part of this targeted systemic response. These small molecules, therefore, offer a viable alternative to achieving desired therapeutic outcomes by interfering with both amyloid and Tau pathways with limited off-target systemic changes.

Synthesis of Novel Magnetic Quercetin-Neuropeptide Nanocomposite as a Smart Nano-Drug Shuttle System: Investigation of Its Effect on Behavior, Histopathological Characteristics, and Expression of MAPT and APP Genes in Alzheimer's Disease Rats.

Alzheimer's disease (AD) is the most common type of dementia. The drugs introduced for this disease have many side effects and limitations in use, so the production of a suitable herbal medicine to cure AD patients is essential. The aim of this research is to make a magnetic neuropeptide nano shuttle as a targeted carrier for the transfer of quercetin to the brains of AD model rats. In this work, a magnetic quercetin-neuropeptide nanocomposite (MQNPN) was fabricated and administered to the rat's brain by the shuttle drug of the Margatoxin scorpion venom neuropeptide, and will be a prospect for targeted drug delivery in AD. The MQNPN has been characterized by FTIR, spectroscopy, FE-SEM, XRD, and VSM. Investigations into the efficacy of MQNPN, MTT, and real Time PCR for MAPT and APP genes expression were performed. After 7 days treatment with Fe3O4 (Ctr) and MQNPN treatment in AD rat, superoxide dismutase activity and quercetin in blood serum and brain was detected. Hematoxylin-Eosin staining was applied for histopathological analysis. Analysis of data showed that MQNPN increased the activity of superoxide dismutase. The histopathology results of the hippocampal region of AD rats also confirmed their improvement after treatment with MQNPN. MQNPN treatment caused a significant decrease in the relative expression of MAPT and APP genes. MQNPN is a suitable carrier for the transfer of quercetin to the rat hippocampus, and has a significant effect in reducing AD symptoms in terms of histopathology, behavioral testing, and changing the expression of AD-related genes.

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study.

We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort. The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data. Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR. Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.

299 Oral difelikefalin improves itch and inflammatory biomarkers in atopic dermatitis subjects with moderate-to-severe pruritus

Pruritus is the most frequent and burdensome atopic dermatitis (AD) symptom and can exacerbate disease via the itch-scratch cycle. Difelikefalin (DFK), a kappa-opioid receptor (KOR) agonist is approved for moderate-to-severe pruritus in adults with CKD undergoing hemodialysis. DFK blocks pruritic signaling through peripheral sensory neurons and may have anti-inflammatory activity. We tested the impact of DFK on pruritus-related and inflammatory transcriptomes of AD patients. In a phase 2 clinical study, subjects with AD and moderate-to-severe pruritus were randomized (1:1:1:1) to receive oral twice-daily DFK (3 doses) or placebo for 12 wk. A substudy (n=40) characterized effects of DFK on pruritus- and AD-related gene expression using baseline and wk 12 skin biopsies. Gene expression was measured using RNA-sequencing and TaqMan Low-Density Array qualitative polymerase chain reaction. Data from DFK groups were pooled. DFK altered expression of multiple individual pruritus- and AD-related genes. Gene set variation analysis confirmed downregulation of pruritus-related genes (eg, IL-31, TRPV2) and the Th2 pathway following 12 wk treatment with DFK, but not placebo. Changes in gene expression of pruritus- and immune-related genes significantly correlated with skin improvement for DFK-treated subjects. DFK downregulated expression of key genes implicated in pruritus and AD inflammation. Reports demonstrate an anti-pruritic effect of DFK in AD and other chronic itch conditions. DFK is a promising therapy for AD-related pruritus and may provide anti-inflammatory benefit by impacting the itch-scratch cycle.

Anthocyanin-rich blackcurrant extract improves long-term memory impairment and emotional abnormality in senescence-accelerated mice.

Alzheimer's disease (AD) is associated with a progressive worsening in cognitive function, which is often accompanied by emotional disturbance. Recent studies revealed that anthocyanin-rich blackcurrant extract (BCE) can impart health benefits, but it is not known whether BCE is useful in the prevention and/or treatment of AD. Here, we examined the effects of BCE using a senescence-accelerated mouse prone 8 (SAMP8) model. Dietary BCE supplementation for 9 weeks was found to both improve the diminished long-term recognition memory and normalize the anxiety levels of SAMP8 mice. RNA sequencing demonstrated that dietary supplementation with anthocyanin-rich BCE significantly altered the gene expression profile in the hippocampus. According to enrichment analysis, genes regulated by BCE were related to cellular component terms such as "smooth endoplasmic reticulum," "axon," and "glutamatergic synapse." Real-time PCR verified alterations in the expression of AD-related genes. These findings indicate that anthocyanin-rich BCE may be valuable for the prevention and/or treatment of AD. PRACTICAL APPLICATIONS: Blackcurrant contains an abundance of polyphenols, especially anthocyanins. This study demonstrated that anthocyanin-rich BCE improves the long-term recognition memory impairment and emotional abnormality of SAMP8 mice, a mouse model characterized by several pathological features of AD. These findings indicate that anthocyanin-rich BCE may be a useful food supplement or ingredient for the prevention of AD.

JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model.

Alzheimer's disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROL™, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.

Alzheimer’s Disease-related Gene Expression Is Reduced Following Six Months Of High-intensity Exercise

Extensive research supports the use of exercise to protect against Alzheimer’s disease (AD). Nevertheless, there is limited evidence from human studies regarding the mechanisms underlying the positive effects of exercise on the brain. Gene expression determines the extent to which a gene is ‘turned on or off’ and can be used to understand mechanistic pathways. Animal research has demonstrated that exercise influences the expression of genes related to various AD biological pathways; however, the impact of exercise on AD-related gene expression has not yet been studied in humans. PURPOSE: To examine changes in AD-related gene expression following a six-month high-intensity exercise intervention. METHODS: Cognitively normal men and women (60-80y) were randomised to either six-months of work-matched high-intensity exercise (n=33), moderate-intensity exercise (n=34) or an inactive control group (n=32). Blood samples were collected pre- and post-intervention and expression levels from a panel of genes implicated in AD were measured. Analysis of covariance (covaried for age and gender), with adjustment for multiple comparisons, was conducted to determine group differences. RESULTS: Decreases in AD-related gene expression following six months of exercise, compared with the control group. More specifically, gene expression associated with cholesterol metabolism (ABCA1; p < 0.001), amyloid precursor protein processing (ADAM17, BACE1; p < 0.05) and synaptic plasticity (UCHL1; p < 0.001) was favourably altered in the high-intensity exercise intervention, compared with the moderate-intensity intervention and control groups. CONCLUSIONS: Investigation of AD-related gene expression has the potential to play an important role in understanding the biological pathways by which exercise reduces AD risk and contributes to enhanced cognitive health. The current work indicates a dose-dependent effect of exercise intensity on the expression of genes associated with AD, revealing mechanistic pathways that require further investigation.

Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD).

To elucidate the key molecules, functions, and pathways that bridge mild cognitive impairment (MCI) and Alzheimer's disease (AD), we investigated open gene expression data sets. Differential gene expression profiles were analyzed and combined with potential MCI- and AD-related gene expression profiles in public databases. Then, weighted gene co-expression network analysis was performed to identify the gene co-expression modules. One module was significantly negatively associated with MCI samples, in which gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that these genes were related to cytosolic ribosome, ribosomal structure, oxidative phosphorylation, AD, and metabolic pathway. The other two modules correlated significantly with AD samples, in which functional and pathway enrichment analysis revealed strong relationships of these genes with cytoplasmic ribosome, protein binding, AD, cancer, and apoptosis. In addition, we regarded the core genes in the module network closely related to MCI and AD as bridge genes and submitted them to protein interaction network analysis to screen for major pathogenic genes according to the connectivity information. Among them, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2), ribosomal protein S3a (RPS3A), S100 calcium binding protein A8 (S100A8), small nuclear ribonucleoprotein polypeptide G (SNRPG), U6 snRNA-associated Sm-like protein LSm3 (LSM3), ribosomal protein S27a (RPS27A), and ATP synthase F1 subunit gamma (ATP5C1) were not only major pathogenic genes of MCI, but also bridge genes. In addition, SNRPD2, RPS3A, S100A8, SNRPG, LSM3, thioredoxin (TXN), proteasome 20S subunit alpha 4 (PSMA4), annexin A1 (ANXA1), DnaJ heat shock protein family member A1 (DNAJA1), and prefoldin subunit 5 (PFDN5) were not only major pathogenic genes of AD, but also bridge genes. Next, we screened for differentially expressed microRNAs (miRNAs) to predict the miRNAs and transcription factors related the MCI and AD modules, respectively. The significance score of miRNAs in each module was calculated using a hypergeometric test to obtain the miRNApivot-Module interaction pair. Thirty-four bridge regulators were analyzed, among which hsa-miR-519d-3p was recognized as the bridge regulator between MCI and AD. Our study contributed to a better understanding of the pathogenic mechanisms of MCI and AD, and might lead to the development of a new strategy for clinical diagnosis and treatment.

Neural Protective Effects of Millet and Millet Polyphenols on High-Fat Diet-Induced Oxidative Stress in the Brain.

A high fat diet (HFD) is considered to be a risk factor for the development of dementia because it increases oxidative stress in the brain; thus, diets rich in antioxidants, such as polyphenols, may protect against oxidative damage. In this study, we explored the antioxidant activity and neural protective function of millet on high fat diet-induced oxidative stress in rat brains. Our results suggested that the intake of millet could alleviate oxidative stress in the hippocampus and downregulate the expression of the Alzheimer's disease (AD)-related genes amyloid precursor protein (App), tau, and γ-secretase. Furthermore, we extracted millet polyphenols and verified whether they play important roles during this process. The results showed that millet polyphenols significantly prevented H2O2-induced cell death of SH-SY5Y cells and decreased oxidative stress levels in cells. In addition, the expression levels of pro-inflammatory factors and AD-related genes were also downregulated by treatment with millet polyphenols. The above results indicated that millet and millet polyphenols could exert neural protective effects under high fat diet-induced oxidative stress by upregulating the expression of antioxidant enzymes and downregulating the expression of AD-related genes.

House dust mite-treated PAR2 over-expressor mouse: A novel model of atopic dermatitis.

Atopic dermatitis (AD) is a complex skin disease involving causative effects from both intrinsic and extrinsic sources. Murine models of the disease often fall short in one of these components and, as a result, do not fully encapsulate these disease mechanisms. We aimed to determine whether the protease-activated receptor 2 over-expressor mouse (PAR2OE) with topical house dust mite (HDM) application is a more comprehensive and clinically representative AD model. Following HDM extract application to PAR2OE mice and controls, AD clinical scoring, itching behaviour, skin morphology and structure, barrier function, immune cell infiltration and inflammatory markers were assessed. Skin morphology was analysed using haematoxylin and eosin staining, and barrier function was assessed by transepidermal water loss measurements. Immune infiltrate was characterised by histological and immunofluorescence staining. Finally, an assessment of AD-related gene expression was performed using quantitative RT-PCR. PAR2OE mice treated with HDM displays all the characteristic clinical symptoms including erythema, dryness and oedema, skin morphology, itch and inflammation typically seen in patients with AD. There is a significant influx of mast cells (P<.01) and eosinophils (P<.0001) into the dermis of these mice. Furthermore, the PAR2OE+HDM mice exhibit similar expression patterns of key differentially expressed genes as seen in human AD. The PAR2OE+HDM mouse presents with a classic AD pathophysiology and is a valuable model in terms of reproducibility and overall disease representation to study the condition and potential therapeutic approaches.

APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer's disease

Alzheimer's disease (AD) primarily affects the brain and is the most common form of dementia worldwide. Despite more than a century of research, there are still no early biomarkers for AD. It has been reported that AD affects the eye, which is more accessible for imaging than the brain; however, links with the cornea have not been evaluated. To investigate whether the cornea could be used to identify possible diagnostic indicators of AD, we analyzed the proteolytic processing and isoforms of amyloid precursor protein (APP) and evaluated the expression of AD-related genes and proteins in corneal fibroblasts from wild-type (WT) corneas and corneas from patients with granular corneal dystrophy type 2 (GCD2), which is related to amyloid formation in the cornea. Reverse transcription polymerase chain reaction (RT-PCR) analysis was used to assess the expression of AD-related genes, i.e., APP, ADAM10, BACE1, BACE2, PSEN1, NCSTN, IDE, and NEP. RT-PCR and DNA sequencing analysis demonstrated that isoforms of APP770 and APP751, but not APP695, were expressed in corneal fibroblasts. Moreover, the mRNA ratio of APP770/APP751 isoforms was approximately 4:1. Western blot analysis also demonstrated the expression of a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), beta-site APP-cleaving enzyme 1 (BACE1), nicastrin, insulin degradation enzyme, and neprilysin in corneal fibroblasts. Among these targets, the levels of immature ADAM10 and BACE1 protein were significantly increased in GCD2 cells. The expression levels of APP, ADAM10, BACE1, and transforming growth factor-beta-induced protein (TGFBIp) were also detected by western blot in human corneal epithelium. We also investigated the effects of inhibition of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems (UPS) on APP processing and metabolism. These pathway inhibitors accumulated APP, α-carboxy-terminal fragments (CTFs), β-CTFs, and the C-terminal APP intracellular domain (AICD) in corneal fibroblasts. Analysis of microRNAs (miRNAs) revealed that miR-9 and miR-181a negatively coregulated BACE1 and TGFBIp, which was directly associated with the pathogenesis of AD and GCD2, respectively. Immunohistochemical analysis indicated that APP and BACE1 were distributed in corneal stroma cells, epithelial cells, and the retinal layer in mice. Collectively, we propose that the cornea, which is the transparent outermost layer of the eye and thus offers easy accessibility, could be used as a potential biomarker for AD diagnosis and progression.

Ameliorating effect of dipotassium glycyrrhizinate on an IL-4- and IL-13-induced atopic dermatitis-like skin-equivalent model.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is not fully understood. Defects in skin barrier function and dysregulation of the Th2 immune response are thought to be pivotal in AD pathogenesis. In this study, we used keratinocytes and AD-like skin equivalent models using Th2 cytokines IL-4 and IL-13. The keratinocytes and AD-like skin model were used to investigate the effect of dipotassium glycyrrhizinate (KG), which is widely used as an anti-inflammatory agent for AD treatment. KG decreased AD-related gene expression in keratinocytes stimulated with Th2 cytokines. KG alleviated AD-like phenotypes and gene expression patterns and inhibited release of AD-related cytokines in the AD-like skin equivalent models. These findings indicate KG has potential effectiveness in AD treatment and AD-like skin equivalent models may be useful for understanding AD pathogenesis.

Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer\u2019s disease

Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an Aβ mouse model of early-onset familial AD.

Histone acetylation maps in aged mice developmentally exposed to lead: epigenetic drift and Alzheimer-related genes.

Early life exposure to lead (Pb) has been shown to increase late life biomarkers involved in Alzheimer's disease (AD) pathology. Here, we tested the hypothesis that latent over expression of AD-related genes may be regulated through histone activation pathways. Chromatin immunoprecipitation sequencing was used to map the histone activation mark (H3K9Ac) to the mouse genome in developmentally Pb exposed mice on postnatal days 20, 270 and 700. Exposure to Pb resulted in a global downregulation of H3K9Ac across the lifespan; except in genes associated with the Alzheimer pathway. Early life exposure to Pb results in an epigenetic drift in H3K9Ac consistent with latent global gene repression. Alzheimer-related genes do not follow this trend.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression

Aging and major depressive disorder are risk factors for dementia, including Alzheimer’s Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression-like behavior in this model.