scholarly journals Aplysia Neurons as a Model of Alzheimer’s Disease: Shared Genes and Differential Expression

2021 ◽  
Author(s):  
Nicholas S. Kron ◽  
Lynne A. Fieber
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Expression ◽  
Late Onset ◽  
The United States ◽  
Data Sets ◽  
Model Of Alzheimer’S Disease ◽  
Neuronal Processes ◽  
Cellular Cargo Transport ◽  
Upregulated Genes

AbstractAlthough Alzheimer’s disease (AD) is the most common form of dementia in the United States, development of therapeutics has proven difficult. Invertebrate alternatives to current mammalian AD models have been successfully employed to study the etiology of the molecular hallmarks of AD. The marine snail Aplysia californica offers a unique and underutilized system in which to study the physiological, behavioral, and molecular impacts of AD. Mapping of the Aplysia proteome to humans and cross-referencing with two databases of genes of interest in AD research identified 898 potential orthologs of interest in Aplysia. Included among these orthologs were alpha, beta and gamma secretases, amyloid-beta, and tau. Comparison of age-associated differential expression in Aplysia sensory neurons with that of late-onset AD in the frontal lobe identified 59 ortholog with concordant differential expression across data sets. The 21 concordantly upregulated genes suggested increased cellular stress and protein dyshomeostasis. The 47 concordantly downregulated genes included important components of diverse neuronal processes, including energy metabolism, mitochondrial homeostasis, synaptic signaling, Ca++ regulation, and cellular cargo transport. Compromised functions in these processes are known hallmarks of both human aging and AD, the ramifications of which are suggested to underpin cognitive declines in aging and neurodegenerative disease.

Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-10
Author(s):  
Wei Qin ◽  
Wenwen Li ◽  
Qi Wang ◽  
Min Gong ◽  
Tingting Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Black People ◽  
Late Onset ◽  
Meta Analysis ◽  
Group Analysis ◽  
Apoe Genotype ◽  
Cochrane Library ◽  
Data Sets ◽  
Apoe Genotypes

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

scholarly journals Genetics of Alzheimer’s Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Perry G. Ridge ◽  
Mark T. W. Ebbert ◽  
John S. K. Kauwe
Keyword(s):  
United States ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Late Onset ◽  
Association Studies ◽  
The United States ◽  
Complex Disorder ◽  
Genetic Components ◽  
Early Onset Alzheimer’S Disease

Alzheimer’s disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer’s disease, early onset and the more common late onset. The genetics of early-onset Alzheimer’s disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer’s disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer’s disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer’s disease.

scholarly journals KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2748
Author(s):  
Tohid Siddiqui ◽  
Prabesh Bhattarai ◽  
Stanislava Popova ◽  
Mehmet Ilyas Cosacak ◽  
Sanjeev Sariya ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Late Onset ◽  
Association Studies ◽  
Neural Regeneration ◽  
Adult Zebrafish ◽  
Amyloid Toxicity ◽  
Model Of Alzheimer’S Disease

Neurogenesis decreases in Alzheimer’s disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.

scholarly journals Genetically regulated expression in late-onset Alzheimer’s disease implicates risk genes within known and novel loci

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hung-Hsin Chen ◽  
Lauren E. Petty ◽  
Jin Sha ◽  
Yi Zhao ◽  
Amanda Kuzma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Meta Analysis ◽  
Data Sets ◽  
Phenotypic Variance ◽  
Risk Variants ◽  
Genome Wide ◽  
Regulated Expression ◽  
Genetic Mechanisms

AbstractLate-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer’s Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer’s Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.

scholarly journals Genetic Markers for Alzheimer's Disease

2015 ◽  
Vol 8 (2) ◽  
Author(s):  
Vanessa Gomes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
The United States ◽  
Chromosome 21 ◽  
Maladie D’Alzheimer ◽  
Chromosome 19 ◽  
Department Of Health ◽  
Services Sociaux ◽  
App Gene

This report aims to inform on the progression of research into the genetic factors involved in the development of Alzheimer’s disease (AD). AD is a life-altering disease that affects millions of individuals from varying races and ethnic backgrounds1. According to the National Institute on Aging, a faculty of the U.S. Department of Health and Human Services, AD has been ranked as the third leading cause of death in the United States, only behind cancer and heart failure. It is predicted that by 2050, approximately one in 45 Americans will be afflicted with the disease5.            Distinctive physical indications of the onset of AD include neuron loss, amyloid plaques and neurofibrillary tangles5. Onset is not frequent prior to 60 years of age but can be caused by one of two reasons. The first is a mutation in the amyloid precursor protein (APP) gene on chromosome 21. This gene is responsible for the regulation of the production of amyloid beta (Aβ) proteins, which are known to be abundant in the brains of AD patients. A mutation in the gene leads to an inappropriate regulation of this protein. The second, and more common cause is a result of an unidentified gene on chromosome 14 in AD patients2. It has been confirmed that there is involvement of chromosome 19 in late onset AD (LOAD)  as well1. Most of the genes that are associated with the development of AD have yet to be identified, but the research is bringing society closer and closer to that goal everyday.Ce rapport vise à fournir de l’information sur la progression de la recherche au sujet des facteurs génétiques impliqués dans le développement de la maladie d'Alzheimer (MA). La MA est une maladie bouleversant la vie de la personne et qui affecte des millions d’individus de diverses races et ethnicité1. Selon l'Institut national sur le vieillissement, un corps professoral du département américain de la santé et des services sociaux, la MA a été classée comme la troisième cause de décès aux États-Unis, ne cédant le pas qu’au cancer et à l'insuffisance cardiaque. Il est prévu que d'ici l'an 2050, environ une personne sur 45 Américains sera affligée avec cette maladie5.Des indications visuelles distinctives de l'apparition de la MA comprennent la perte des neurones, les plaques amyloïdes et des enchevêtrements neurofibrillaires5. L'apparition précoce n’est pas fréquente avant 60 ans, mais peut être causée par l'une des deux raisons. La première raison est une mutation dans le gène de la protéine précurseur de l'amyloïde (PPA) sur le chromosome 21. Ce gène est responsable de la régulation de la production de protéines bêta-amyloïde (Aß), qui sont connues pour être abondant dans le cerveau des patients atteints de la MA. Une mutation dans le gène conduit à une régulation inappropriée de cette protéine. La seconde cause, et celle-là plus communes sont le résultat d'un gène inconnu sur le chromosome 142. Il a été confirmé qu'il y a aussi une participation du chromosome 19 dans l'apparition tardive de la MA (ATMA)1. La plupart des gènes qui sont associés avec le développement de la MA n’ont pas encore été identifiés, mais la recherche rapproche la société de cet objectif de plus en plus tous les jours.

scholarly journals Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer’s Disease

2021 ◽  
Author(s):  
Jack Hashem ◽  
Mei Hu ◽  
Jian Zhang ◽  
Fei Gao ◽  
Chu Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Therapeutic Target ◽  
The United States ◽  
Synaptic Proteins ◽  
Spatial Learning And Memory ◽  
Memory Retention ◽  
Model Of Alzheimer’S Disease ◽  
Tau Mouse Model

Abstract Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the United States. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates b-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated tau, and GSK3b in P301S/PS19 mice, a tau mouse model of AD. Importantly, Tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.

scholarly journals Good problems to have? Policy and societal implications of a disease-modifying therapy for presymptomatic late-onset Alzheimer’s disease

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Misha Angrist ◽  
Anna Yang ◽  
Boris Kantor ◽  
Ornit Chiba-Falek
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Editing ◽  
Late Onset ◽  
The United States ◽  
Societal Implications ◽  
Track Record ◽  
Disease Modifying Therapy ◽  
The Us ◽  
Disease Modifying

Abstract In the United States alone, the prevalence of AD is expected to more than double from six million people in 2019 to nearly 14 million people in 2050. Meanwhile, the track record for developing treatments for AD has been marked by decades of failure. But recent progress in genetics, neuroscience and gene editing suggest that effective treatments could be on the horizon. The arrival of such treatments would have profound implications for the way we diagnose, triage, study, and allocate resources to Alzheimer’s patients. Because the disease is not rare and because it strikes late in life, the development of therapies that are expensive and efficacious but less than cures, will pose particular challenges to healthcare infrastructure. We have a window of time during which we can begin to anticipate just, equitable and salutary ways to accommodate a disease-modifying therapy Alzheimer’s disease. Here we consider the implications for caregivers, clinicians, researchers, and the US healthcare system of the availability of an expensive, presymptomatic treatment for a common late-onset neurodegenerative disease for which diagnosis can be difficult.

scholarly journals α-Tocopherol Modulates Non-Amyloidogenic Pathway and Autophagy in an In Vitro Model of Alzheimer’s Disease: A Transcriptional Study

2019 ◽  
Vol 9 (8) ◽  
pp. 196 ◽  
Author(s):  
Agnese Gugliandolo ◽  
Luigi Chiricosta ◽  
Serena Silvestro ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloidogenic Processing ◽  
Model Of Alzheimer’S Disease ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
Vitro Model ◽  
Upregulated Genes

Alzheimer’s disease (AD) is the most common form of dementia worldwide. The hallmarks of AD are the extracellular amyloid plaques, which are formed by amyloid β (Aβ) aggregates derived from the processing of the amyloid precursor protein (APP), and the intraneuronal neurofibrillary tangles, which are formed by the hyperphosphorylated tau protein. The aim of this work was to study the effects of α-tocopherol in retinoic acid differentiated SH-SY5Y neuroblastoma cells exposed to Aβ1-42 evaluating the transcriptional profile by next-generation sequencing. We observed that α-tocopherol was able to reduce the cytotoxicity induced by Aβ treatment, as demonstrated by Thiazolyl Blue Tetrazolium Bromide (MTT) assay. Moreover, the transcriptomic analysis evidenced that α-tocopherol treatment upregulated genes involved in the non-amyloidogenic processing of APP, while it downregulated the amyloidogenic pathway. Moreover, α-tocopherol modulated the expression of the genes involved in autophagy and the cell cycle, which are both known to be altered in AD. The treatment with α-tocopherol was also able to reduce oxidative stress, restoring nuclear factor erythroid-derived 2-like 2 (Nrf2) and decreasing inducible nitric oxide synthase (iNOS) levels, as demonstrated by immunocytochemistry.

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