scholarly journals Generating Late-Onset Human iPSC-Based Disease Models by Inducing Neuronal Age-Related Phenotypes through Telomerase Manipulation

Cell Reports ◽  
2016 ◽  
Vol 17 (4) ◽  
pp. 1184-1192 ◽  
Author(s):  
Elsa Vera ◽  
Nazario Bosco ◽  
Lorenz Studer
Keyword(s):  
Late Onset ◽  
Disease Models ◽  
Age Related ◽  
Human Ipsc

scholarly journals Generation of three human iPSC lines from patients with a spontaneous late-onset Alzheimer’s disease and three sex- and age-matched healthy controls

2021 ◽  
Vol 53 ◽  
pp. 102378
Author(s):  
Jan Raska ◽  
Hana Klimova ◽  
Katerina Sheardova ◽  
Veronika Fedorova ◽  
Hana Hribkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Healthy Controls ◽  
Human Ipsc

scholarly journals Direct Neuronal Reprogramming of Common Marmoset Fibroblasts by ASCL1, microRNA-9/9*, and microRNA-124 Overexpression

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 6
Author(s):  
Akisa Nemoto ◽  
Reona Kobayashi ◽  
Sho Yoshimatsu ◽  
Yuta Sato ◽  
Takahiro Kondo ◽  
...  
Keyword(s):  
Late Onset ◽  
Common Marmoset ◽  
Cellular Level ◽  
Biomedical Science ◽  
Disease Models ◽  
Specific Gene ◽  
Bhlh Transcription Factor ◽  
Research Fields ◽  
Microrna 124

The common marmoset (Callithrix jacchus) has attracted considerable attention, especially in the biomedical science and neuroscience research fields, because of its potential to recapitulate the complex and multidimensional phenotypes of human diseases, and several neurodegenerative transgenic models have been reported. However, there remain several issues as (i) it takes years to generate late-onset disease models, and (ii) the onset age and severity of phenotypes can vary among individuals due to differences in genetic background. In the present study, we established an efficient and rapid direct neuronal induction method (induced neurons; iNs) from embryonic and adult marmoset fibroblasts to investigate cellular-level phenotypes in the marmoset brain in vitro. We overexpressed reprogramming effectors, i.e., microRNA-9/9*, microRNA-124, and Achaete-Scute family bHLH transcription factor 1, in fibroblasts with a small molecule cocktail that facilitates neuronal induction. The resultant iNs from embryonic and adult marmoset fibroblasts showed neuronal characteristics within two weeks, including neuron-specific gene expression and spontaneous neuronal activity. As directly reprogrammed neurons have been shown to model neurodegenerative disorders, the neuronal reprogramming of marmoset fibroblasts may offer new tools for investigating neurological phenotypes associated with disease progression in non-human primate neurological disease models.

scholarly journals Methylation Marks of Blood Leukocytes of Native Hucul Mares Differentiated in Age

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
T. Ząbek ◽  
E. Semik-Gurgul ◽  
T. Szmatoła ◽  
A. Gurgul ◽  
A. Fornal ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Late Onset ◽  
Advanced Age ◽  
Farm Animals ◽  
Blood Leukocytes ◽  
Data Set ◽  
Reduced Representation ◽  
Age Related ◽  
Reduced Representation Bisulfite Sequencing ◽  
Cellular Signal

Horses are one of the longest-living species of farm animals. Advanced age is often associated with a decrease in body condition, dysfunction of immune system, and late-onset disorders. Due to this, the search for new solutions in the prevention and treatment of pathological conditions of the advanced age of horses is desirable. That is why the identification of aging-related changes in the horse genome is interesting in this respect. In the recent years, the research on aging includes studies of age-related epigenetic effects observed on the DNA methylation level. We applied reduced representation bisulfite sequencing (RRBS) to uncover a range of age DMR sites in genomes of blood leukocytes derived from juvenile and aged horses of native Hucul breed. Genes colocated with age-related differentially methylated regions (age DMRs) are the members of pathways involved in cellular signal transduction, immune response, neurogenesis, differentiation, development, and cancer progression. A positive correlation was found between methylation states and gene expression in particular loci from our data set. Some of described age DMR-linked genes were also reported elsewhere. Obtained results contribute to the knowledge about the molecular basis of aging of equine blood cells.

scholarly journals Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 446
Author(s):  
Jennifer T. Saville ◽  
Maria Fuller
Keyword(s):  
Pompe Disease ◽  
Late Onset ◽  
Reference Interval ◽  
Laboratory Diagnosis ◽  
Reference Intervals ◽  
Confirmatory Test ◽  
Diagnostic Laboratory ◽  
Age Related ◽  
Initial Drop ◽  
Monitoring Treatment

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation.

P1-131: MODEL-AD: LATE-ONSET ALZHEIMER'S DISEASE MODELS

2006 ◽  
Vol 14 (7S_Part_5) ◽  
pp. P321-P321
Author(s):  
Bruce T. Lamb ◽  
Adrian L. Oblak ◽  
Harriet M. Williams ◽  
David Baglietto-Vargas ◽  
Marcelo A. Wood ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Disease Models

scholarly journals Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease

2020 ◽  
Author(s):  
Megan M. Senchuk ◽  
Jeremy M. Van Raamsdonk ◽  
Darren J. Moore
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lifespan Extension ◽  
Disease Manifestation ◽  
Genetic Pathways ◽  
Dopaminergic Neurodegeneration ◽  
Age Related ◽  
Increased Risk ◽  
Extended Longevity

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

scholarly journals APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Zhao ◽  
Yuan Fu ◽  
Yu Yamazaki ◽  
Yingxue Ren ◽  
Mary D. Davis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Subject ◽  
Late Onset ◽  
Disease Patient ◽  
Underlying Mechanism ◽  
Synapse Loss ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
Normal Cognition

Abstract APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

scholarly journals Perspectives for metabolomics in testosterone replacement therapy

2012 ◽  
Vol 215 (1) ◽  
pp. 3-16 ◽  
Author(s):  
Robin Haring
Keyword(s):  
Replacement Therapy ◽  
Biomarker Discovery ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Disease Diagnosis ◽  
Deficiency Syndrome ◽  
Testosterone Replacement ◽  
Testosterone Replacement Therapy ◽  
Age Related ◽  
Pubmed Database

Testosterone is the major circulating androgen in men but exhibits an age-related decline in the ageing male. Late-onset hypogonadism or androgen deficiency syndrome (ADS) is a ‘syndromic’ disorder including both a persistent low testosterone serum concentration and major clinical symptoms, including erectile dysfunction, low libido, decreased muscle mass and strength, increased body fat, decreased vitality or depressed mood. Given its unspecific symptoms, treatment goals and monitoring parameters, this review will outline the various uncertainties concerning the diagnosis, therapy and monitoring of ADS to date. Literature was identified primarily through searches for specific investigators in the PubMed database. No date or language limits were applied in the literature search for the present review. The current state of research, showing that metabolomics is starting to have an impact not only on disease diagnosis and prognosis but also on drug treatment efficacy and safety monitoring, will be presented, and the application of metabolomics to improve the clinical management of ADS will be discussed. Finally, the scientific opportunities presented by metabolomics and other -omics as novel and promising tools for biomarker discovery and individualised testosterone replacement therapy in men will be explored.

O3-04-03: Age-Related Neuropathology Helps Distinguish Autosomal Dominant from Late-Onset Alzheimer's Disease

2016 ◽  
Vol 12 ◽  
pp. P291-P292
Author(s):  
Nigel J. Cairns ◽  
Richard J. Perrin ◽  
Erin E. Franklin ◽  
Benjamin D. Vincent ◽  
Michael Baxter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Age Related
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