scholarly journals Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Hsueh-Te Lee ◽  
Kuan-I Lee ◽  
Chia-Hui Chen ◽  
Tzong-Shyuan Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Translational Regulation ◽  
Epoxide Hydrolase ◽  
Cell Types ◽  
Soluble Epoxide Hydrolase ◽  
Small Gtpase ◽  
Activated T Cells ◽  
Genetic Ablation ◽  
The Brain

Abstract Background Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear. Methods To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH−/−) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH−/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches. Results We demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH−/− mice compared with APP/PS1 Tg mice. Conclusion Our results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

scholarly journals Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.

1996 ◽  
Vol 44 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
P J McMillan ◽  
J B Leverenz ◽  
P Poorkaj ◽  
G D Schellenberg ◽  
D M Dorsa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Basal Forebrain ◽  
Cell Types ◽  
Hybridization Histochemistry ◽  
In Situ Hybridization Histochemistry ◽  
A Cell ◽  
The Brain

Mutations in the STM2 gene cause familial Alzheimer's disease (AD) in Volga Germans. To understand the function of this protein and how mutations lead to AD, it is important to determine which cell types in the brain express this gene. In situ hybridization histochemistry indicates that STM2 expression in the human brain is widespread and is primarily neuronal. In addition, STM2 mRNA is expressed in a cell line with neuronal origins. Quantification of the level of expression of the STM2 message in the basal forebrain, frontal cortex, and hippocampus reveals a significant decrease in AD-affected subjects compared to normal age-matched controls. These data suggest that downregulation of neuronal STM2 gene expression may be involved in the progression of AD.

scholarly journals Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase and ethanolamides metabolism with Alzheimer’s disease

2021 ◽  
Author(s):  
Kamil Borkowski ◽  
Theresa L. Pedersen ◽  
Nicholas T. Seyfried ◽  
James J. Lah ◽  
Allan I. Levey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cytochrome P450 ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Lipid Mediators ◽  
Partial Least Square ◽  
Pharmacological Intervention ◽  
Healthy Controls

Abstract Background Alzheimer’s disease, cardiovascular disease and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids regulate inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their roles in Alzheimer’s disease and their potential as biomarkers are poorly understood. Here we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of individuals with Alzheimer’s disease and healthy controls to investigate these knowledge gaps. Methods Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression. Results In both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Conclusions Previous studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease, yielding potential biomarkers of the disorder. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

scholarly journals Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2513
Author(s):  
Maria Calvo-Rodriguez ◽  
Elizabeth K. Kharitonova ◽  
Brian J. Bacskai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Therapeutic Strategies ◽  
Neuronal Function ◽  
Calcium Dysregulation ◽  
Disease Mechanisms ◽  
Chemical Agents ◽  
The Brain ◽  
Ca2 Channels

Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people worldwide. Unfortunately, none of the current treatments are effective at improving cognitive function in AD patients and, therefore, there is an urgent need for the development of new therapies that target the early cause(s) of AD. Intracellular calcium (Ca2+) regulation is critical for proper cellular and neuronal function. It has been suggested that Ca2+ dyshomeostasis is an upstream factor of many neurodegenerative diseases, including AD. For this reason, chemical agents or small molecules aimed at targeting or correcting this Ca2+ dysregulation might serve as therapeutic strategies to prevent the development of AD. Moreover, neurons are not alone in exhibiting Ca2+ dyshomeostasis, since Ca2+ disruption is observed in other cell types in the brain in AD. In this review, we examine the distinct Ca2+ channels and compartments involved in the disease mechanisms that could be potential targets in AD.

scholarly journals The neuroinflammatory interleukin-12 signaling pathway drives Alzheimer’s disease-like pathology by perturbing oligodendrocyte survival and neuronal homeostasis

2021 ◽  
Author(s):  
Shirin Schneeberger ◽  
Seung Joon Kim ◽  
Pascale Eede ◽  
Anastasiya Boltengagen ◽  
Caroline Braeuning ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Amyloid Β ◽  
Cell Types ◽  
Interleukin 12 ◽  
Genetic Ablation ◽  
Neuronal Homeostasis ◽  
Chronic Neuroinflammation ◽  
Main Driver

AbstractAlzheimer’s disease (AD) is characterized by deposition of pathological amyloid-β (Aβ) and tau protein aggregates and involves chronic neuroinflammation, ultimately leading to neurodegeneration and cognitive decline. Central in AD-related neuroinflammation is the proinflammatory interleukin-12 (IL-12)/IL-23 signaling pathway whose inhibition has been shown to attenuate pathology and cognitive defects in AD-like mice. In order to explore which cell types are involved in this neuroinflammatory cascade, we used single-nuclei RNA sequencing in AD-like APPPS1 mice lacking or harboring IL-12/IL-23 signaling. We found Il12b transcripts encoding the common p40 subunit of IL-12/IL-23 signaling to be expressed preferentially, but not exclusively, in microglia in an AD-specific manner. In contrast, transcripts for the other subunits of the IL-12 signaling pathway were expressed constitutively in neurons and oligodendrocytes irrespective of AD pathology, while transcripts for IL-23 were almost undetectable. Notably, genetic ablation of IL-12/IL-23 signaling did not affect the inflammatory gene expression profile of the AD-specific disease associated microglia (DAM), but reversed the loss of mature myelin-producing oligodendrocytes and alterations in neuronal homeostasis in APPPS1 mice. Taken together, our results reveal that IL-12, but not IL-23 is the main driver of AD-specific IL-12/IL-23 neuroinflammation, which alters neuronal and oligodendrocyte functions. Given that drugs targeting IL-12 already exist, our data may foster first clinical trials in AD subjects using this novel neuroimmune target.

scholarly journals Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Kamil Borkowski ◽  
Theresa L. Pedersen ◽  
Nicholas T. Seyfried ◽  
James J. Lah ◽  
Allan I. Levey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cytochrome P450 ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Lipid Mediators ◽  
Partial Least Square ◽  
Pharmacological Intervention ◽  
Healthy Controls

Abstract Background Alzheimer’s disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer’s disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case–control comparison of ~150 individuals with Alzheimer’s disease and ~135 healthy controls, to investigate this knowledge gap. Methods Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression. Results In both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Conclusions Previous studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

scholarly journals USING NEURAL NETWORK TO UNCOVER CELL TYPES THROUGH SNRNA SEQUENCING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S834-S834
Author(s):  
Fahad Paryani ◽  
Vilas Menon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Learning Approaches ◽  
Post Mortem Brain ◽  
Single Nucleus ◽  
General Classifier ◽  
Classification Tool ◽  
Genetic Signatures ◽  
The Brain

Abstract The advent of single-nucleus RNA-sequencing (snRNAseq) has allowed for the exploration of genetic signatures of the numerous cells in the brain. In particular, snRNAseq data can provide new insights into how many neurodegenerative diseases, such as Alzheimer’s Disease, alter cells in the brain. One major challenge with analyzing snRNAseq data is the lack of a systematic way to classify the various cell types across different datasets. To address this challenge, we developed a general classifier (“DeepSeq”) that uses state-of-the-art deep learning approaches. We trained our model on multiple snRNAseq datasets derived from post-mortem brain tissue in individuals with and without clinical diagnosis of Alzheimer’s Disease from the ROSMAP cohorts. The two snRNAseq datasets contained 70,064 nuclei and 170,275 nuclei. The two studies employed different clustering techniques, and identified 44 and 18 putative cell types. To map these disparate cluster identities across datasets, we extracted the most relevant genes and trained two separate networks, one on each dataset. We then validated each classifier separately on the holdout cells. The resulting classifier accuracy were 87% and 94%. To map clusters across datasets, we then applied each classifier to the other dataset. Both classifiers yielded mappings that reflected the overall biology, correctly categorizing the nuclei into broad and fine cell type classes. Although validation on additional datasets would expand the generality of this approach, our results show that DeepSeq is an easily implementable classification tool that can assign identity to nuclei in new snRNAseq datasets without the need for preprocessing or cross-batch alignment.

scholarly journals Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

2019 ◽  
Author(s):  
Christian Griñán-Ferré ◽  
Sandra Codony ◽  
Eugènia Pujol ◽  
Jun Yang ◽  
Rosana Leiva ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Age Related ◽  
Novel Target ◽  
Age Related Cognitive Decline

AbstractThe inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with two compounds that have entered clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer’s Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques. Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

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