Investigating the role of p16 and cellular senescence in Alzheimer’s disease pathogenesis
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ABSTRACT:
PROVIDER: PRJNA1057837 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27368437_1.fastq.gz | Fastqsanger.gz | |||
| SRR27368437_2.fastq.gz | Fastqsanger.gz | |||
| SRR27368438_1.fastq.gz | Fastqsanger.gz | |||
| SRR27368438_2.fastq.gz | Fastqsanger.gz | |||
| SRR27368439_1.fastq.gz | Fastqsanger.gz |
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Project description:Advancing age is the greatest risk factor for Alzheimer’s Disease (AD), as most AD patients are age 65 and older. However, the mechanistic contribution of aging to AD is unclear. Cellular senescence, one of the major hallmarks of aging, is recently implicated as an aggravator of AD pathogenesis. The critical senescence regulator p16 is increased in neurons of AD patients and mouse models. Eliminating p16-expressing senescent cells attenuates AD pathologies in AD mouse models. However, what p16 does in post-mitotic neurons and how p16 contributes to AD pathogenesis remains unknown. As clinical trials continually fail to improve cognitive decline in AD patients, it is increasingly important to develop a better human cell-based model system to advance our understanding of the impact of aging in AD pathogenesis. Induced pluripotent stem cell (iPSC) technology has revolutionized human disease modeling, enabling differentiation to relevant brain cell types for the study of AD pathogenesis in a human cell-based culture environment. AD iPSC-derived neurons exhibit higher levels of Amyloid beta secretion and tau phosphorylation compared to non-demented control iPSC-derived neurons. Nevertheless, iPSC-derived neurons are “fetal-like” and fail to recapitulate the aging process in AD pathogenesis. Thus, we have developed a robust human iPSC-based neuron model to investigate the contribution of p16 expression to cellular senescence and AD pathogenesis. We found that inducible p16 expression leads to senescence phenotypes in AD as well as non-demented control iPSC-derived neurons. The impact of p16 and induced senescence in neurons on the cellular pathologies of AD is investigated. Our study provides a novel approach to investigate aging-associated cellular changes that potentially influence AD patient-derived differentiated neurons to age and become more permissive to AD pathogenesis in culture.
2023-12-31 | GSE252132 | GEO
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells. TIG-3 ER-p16 cells (primary normal human diploid fibroblasts expressing a 4-hydroxytamoxifen(4-OHT) regulatable form of human p16) were cultured for 7 days with or without 4-OHT. Total RNA was isolated using TRIzol reagent and were analyzed using the hum
2014-04-10 | E-GEOD-49863 | biostudies-arrayexpress
Project description:We performed the single cell RNA sequencing of mouse normal kidney, normal liver, and NASH-induced liver from p16-tdTomato mice. In order to enrich p16 positive cells, we independently sorted the non-separated cells (including both of p16 positive and negative cells) and p16 positive cells alone through tdTomato intensity by FACS. By obtaining 13,876 single cell transcripts, after the graph-based clustering and marker genes defined cell type classification, we identified the heterogeneity of in vivo p16-positive cells which dispersedly existed in renal cells and non-parenchymal hepatic cells. Differential expressing genes (DEGs) comparisons for each cell type were feasible to study the in vivo p16 dependent transcriptomic pattern change. Finally, we verified several cell type specific senescence-like phenotypes which were previously found on in vitro cellular senescence, and also identified the p16-related subpopulation which might involve in NASH progression and renal damage response.
2020-09-16 | GSE155182 | GEO
Project description:p16 and p21 act as tumor suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not known. To identify the mechanism responsible for the failure of Mo-MDSCs (monocytic myeloid-derived suppressor cells) infiltration into tumor allografts in p16/p21-double knockout (DKO) mice, we searched for chemokine receptors that were highly expressed in Mo- but not PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells) and were downregulated in p16/p21-DKO as compared to WT Mo-MDSCs. Ccr2, Ccr5, and Cx3cr1 were identified by RNA-seq analysis.
2018-02-13 | GSE93359 | GEO
Project description:Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, potentially of major clinicopathological relevance, are unknown. A major stumbling block to studying senescence has been the absence of suitable model systems because of the asynchrony of this process in heterogeneous cell populations. To simplify this process many investigators study oncogene-induced senescence due to expression of activated oncogenes where senescence occurs prematurely without telomere attrition and can be induced acutely in a variety of cell types. We have taken a different approach by making use of the finding that reconstitution of telomerase activity by introduction of the catalytic subunit of human telomerase alone is incapable of immortalising all human somatic cells, but inactivation of the p16-pRB and p53-p21 pathways are required in addition. The ability of SV40 large T antigen to inactivate the p16-pRB and p53-p21 pathways has enabled us to use a thermolabile mutant of LT antigen, in conjunction with hTERT, to develop conditionally immortalised human (HMF3A) fibroblasts that are immortal but undergo an irreversible growth arrest when the thermolabile LT antigen is inactivated leading to activation of pRB and p53. When these cells cease dividing, senescence-associated- b-galactosidase activity is induced and the growth-arrested cells have morphological features and express genes in common with senescent cells. Since these cells growth arrest in a synchronous manner they are an excellent starting point for dissecting the pathways that underlie cellular senescence and act downstream of p16-pRB and p53-p21 pathways. We have combined genome-wide expression profiling with genetic complementation to undertake identification of genes that are differentially expressed when these conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. Genes differentially expressed upon senescence will be identified by comparing arrays from growing versus senescent cells. Changes in gene expression due to the temperature shift will be eliminated by comparing with array data from the non-conditional HMF3S cells grown at 34°C ±0.5°C and 38°C ±0.5°C. To determine if the changes in gene expression upon senescence are specific and reversible, the set of differential genes will then be overlaid with array data from cells in which senescence has been bypassed by inactivation of the p16-pRB and p53-p21 tumour suppressor pathways
2011-01-21 | E-GEOD-24810 | biostudies-arrayexpress
Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.
2024-03-20 | GSE231332 | GEO
Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells. Neonatal mice were injected with RCAS PDGFB GFP. At symptoms, or at 12 weeks post injection, GFP+DAPI- tumor cells were sorted for RNA extraction and hybridization on Affymetrix microarrays. The mouse strain used was a mixed background of C57/BL6 and FVB/N. Ptprd mice were from Uetani et al. 2000 and p16/Nestin-tvA mice were from Tchouganouva et al. 2007.
2014-06-02 | E-GEOD-55061 | biostudies-arrayexpress
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells.
2014-04-10 | GSE49863 | GEO
Project description:The strongest risk factors for Alzheimer’s disease (AD) include the 4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that the R47H variant induces neurodegeneration in 9- to- 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.
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