Early-Onset Hearing Loss in Mouse Models of Alzheimer’s Disease correlates to DNA Damage in Cochlea
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PROVIDER: PRJNA971213 | ENA |
REPOSITORIES: ENA
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Project description:Alzheimer's disease (AD) is the most common type of dementia and is characterized by cognitive and behavioral impairment that significantly interferes with social functioning. Over the last decade, there has been an increased interest in whether sensory deficiency may be associated with the development of AD. Notably, the relationship between hearing impairment and AD is of great relevance, but still poorly understood. In this study, we found an early-onset hearing loss in 3xTgAD and 3xTgAD/Polβ+/− mouse models. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings. Herein, we report that both 3xTgAD and 3xTgAD/Polβ+/− mice showed increased ABR thresholds between at 16 and 32 kHz at 4 weeks of age, much earlier than any AD behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/− mice than in 3xTgAD mice at 16 kHz, and DPOAE signals were also reduced, indicating that DNA damage may affect hearing impairment in AD. Poly ADP-ribosylation levels and protein expression of DNA damage markers increased significantly and NAD+ levels were reduced in the cochlea of 3xTgAD and 3xTgAD/Polβ+/− mice. Remarkably, we observed the downregulation of phosphoglycerate mutase 2 (PGAM2) in cochlea and a decrease in the number of synaptic ribbons in the presynaptic zones of inner hair cells in 3xTgAD/Polβ+/− mice. We also find that the activity of sirtuin 3 (SIRT3) is downregulated in cochlea, indicative of impaired mitochondrial function. Taken together, hearing impairment may be a potential early marker of AD. In addition, these findings provide new insights into the mechanism of the relationship between hearing dysfunction and AD and suggest that DNA damage in the cochlea can contributes to the development of early hearing loss of AD. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) at 4 weeks of age, thereafter whole cochlea and auditory cortex tissue were collected from each mouse (WT, Polβ+/−, 3xTgAD, and 3xTgAD/Polβ+/−) and subjected to total RNA isolation to understand what metabolism-related gene expression changes in cochlea and auditory cortex.
2024-03-27 | GSE232205 | GEO
Project description:Our work describes the application of mass spectrometry-based label-free quantitative proteomics for the identification of differentially expressed proteins between different-aged cochlea. We report proteins exclusively present as well as up- and downregulated in the cochlear sensory epithelium at significant developmental stages. Additionally, we report proteins exclusively present on P3 that were recently identified in the cochlea for the first time. We use bioinformatics to provide insight on biological functions and potential primary and secondary partners of the differentially expressed proteins. This study provides the first differentially expressed proteome in the mammalian cochlea at significant developmental stages; before hearing, during the onset of hearing, and when hearing is fully developed. We believe that these results will provide insights into the function of proteins that change during development and identify potential protein biomarkers related to hearing impairments.
2018-08-29 | PXD001973 | Pride
Project description:Age-related hearing loss (AHL) is the progressive loss of auditory function with aging. The DBA/2J (DBA) mice have been used as a model of AHL and undergoes progressive, age-related hearing loss by 12 weeks of age. Here we analyzed cochlear gene expression of 7-week-old and 36-week-old DBA mice using microarrays. Auditory brainstem response (ABR) analysis confrimed that severe age-related hearing loss occured in 36-week-old mice, whereas moderate hearing loss occured in 7-week-old mice. Comprehensive gene expression analysis identified genes correlated with AHL and revealeed that 15 mitochondrial process categories, including â??mitochondrial electron transport chainâ??, â??oxidative phosphorylationâ??, â??respiratory chain complex Iâ??, â??respiratory chain complex IVâ??, and â??respiratory chain complex Vâ??, were statistically associated with AHL-correlated genes in the cochlea of 36-week-old DBA mice, and that 25 genes encoding components of the mitochondrial respiratory chain (respiratory chain complex I, IV, and V) were significantly down-regulated in the cochlea. These observations provide evidence that AHL is associated with down-regulation of genes involved in the mitochondrial respiratory chain in the cochlea of DBA mice, and suggest that mitochondrial respiratory chain dysfunction may be a key feature of AHL in mammalian cochlea. Experiment Overall Design: To determine the effects of age-related hearing loss, each 7-week-old sample (n = 3) was compared to each 36-week-old sample (n = 3), generating a total of nine pairwise comparisons. Using DAVIS and EASE, the identified genes were assign to â??GO: Biological Processâ?? categories of Gene Ontology Consortium. Furthermore, we used EASE to determine the total number of genes that were assigned to each biological process category, and to perform Fisher exact test. Quality control measures were not used. No replicates were done. Dye swap was not used.
2008-06-14 | E-GEOD-6045 | biostudies-arrayexpress
Project description:Age-related hearing loss (AHL) is the progressive loss of auditory function with aging. The DBA/2J (DBA) mice have been used as a model of AHL and undergoes progressive, age-related hearing loss by 12 weeks of age. Here we analyzed cochlear gene expression of 7-week-old and 36-week-old DBA mice using microarrays. Auditory brainstem response (ABR) analysis confrimed that severe age-related hearing loss occured in 36-week-old mice, whereas moderate hearing loss occured in 7-week-old mice. Comprehensive gene expression analysis identified genes correlated with AHL and revealeed that 15 mitochondrial process categories, including “mitochondrial electron transport chain”, “oxidative phosphorylation”, “respiratory chain complex I”, “respiratory chain complex IV”, and “respiratory chain complex V”, were statistically associated with AHL-correlated genes in the cochlea of 36-week-old DBA mice, and that 25 genes encoding components of the mitochondrial respiratory chain (respiratory chain complex I, IV, and V) were significantly down-regulated in the cochlea. These observations provide evidence that AHL is associated with down-regulation of genes involved in the mitochondrial respiratory chain in the cochlea of DBA mice, and suggest that mitochondrial respiratory chain dysfunction may be a key feature of AHL in mammalian cochlea. Keywords: Disease state analysis, Time course analysis
2007-10-16 | GSE6045 | GEO
Project description:To identify which miRNAs are involved in the onset and progression of age-related hearing loss in the mammalian cochlea We used miRNA microarrays to screen the miRNAs which exhibit the drastic changes in their expressing level during the aging of the cochlea The organ of Corti (OC), the major pathological sites of presbycusis in cochlea, was collected separately at 3 timepoints during the life span. Two strains were selected: C57bl/6j (as accelerated prebycusis model) and CBA/J (as naturally occured presbycusis model). The selected timepoints were: Postnatal 21 days (P21), 3 month (3m) and 9 month (9m) for C57 mice, and P21, 9m, 16m for CBA mice.
2013-03-12 | E-GEOD-45026 | biostudies-arrayexpress
Project description:Various organ failure induced by chronic intake of GeO2 is one of the well known disease related to mitochondrial dysfunction. The 0.15% GeO2 treated CBA mice shows severe hearing loss in 4M. Here we analyzed cochlear gene expression of 6 months old CBA mice using microarrays treated with normal chow or that containing 0.15% GeO2 for four months. Auditory brainstem response (ABR) analysis confirmed that severe age-related hearing loss occured in GeO2 treated mice, whereas no hearing loss occured in normal chow treated mice. Comprehensive gene expression analysis identified genes correlated with GeO2-induced mithochodrial dysfunction genes and revealed that 28 genes encoding components of the mitochondrial respiratory chain were significantly down-regulated. These observations provide evidence that GeO2-induced hearing loss is associated with the down-regulation of genes involved in the mitochondrial respiratory chain complexes in the cochlea of CBA mice.
2016-07-22 | GSE84735 | GEO
Project description:Various organ failure induced by chronic intake of GeO2 is one of the well known disease related to mitochondrial dysfunction. The 0.15% GeO2 treated CBA mice shows severe hearing loss in 4M. Here we analyzed cochlear gene expression of 6 months old CBA mice using microarrays treated with normal chow or that containing 0.15% GeO2 for four months. Auditory brainstem response (ABR) analysis confirmed that severe age-related hearing loss occured in GeO2 treated mice, whereas no hearing loss occured in normal chow treated mice. Comprehensive gene expression analysis identified genes correlated with GeO2-induced mithochodrial dysfunction genes and revealed that 28 genes encoding components of the mitochondrial respiratory chain were significantly down-regulated. These observations provide evidence that GeO2-induced hearing loss is associated with the down-regulation of genes involved in the mitochondrial respiratory chain complexes in the cochlea of CBA mice. To determine the effects of GeO2, each control sample (n=5) was compared to each GeO2-intoxicated (n=5), generating a total of 25 pairwise comparisons. Using DAVIS and EASE, the identified genes were assign to GO: Biological Process categories of Gene Ontology Consortium. Furthermore, we used EASE to determine the total number of genes that were assigned to each biological process category, and to perform Fisher exact test. Quality control measures were not used. No replicates were done. Dye swap was not used.
2016-07-22 | E-GEOD-84735 | biostudies-arrayexpress
Project description:Noise-induced hidden hearing loss (HHL) is a new type of hearing loss that has been identified in recent years and leads to insidious damage to the cochlea, unlike the well-known noise-induced hearing loss (NIHL). However, the cellular and molecular basis for it remains to be elucidated. Here, we established a single-cell transcriptome profile of the C57BL/6J mouse cochlea, in which we describe the transcriptome changes of individual cell types within the cochlea with HHL and NIHL. Mice in the HHL group were exposed to 110 dB of noise for 2 hours, and those in the NIHL group were exposed to 115 dB of noise for 4 hours for 3 days. The cochlea was taken 6 hours after the last noise exposure. The control group was not exposed to noise, with other conditions being the same as those in the noise-exposed group. The results of sequencing at the single-cell level help us gain a deeper understanding of the mechanisms of the development of HHL and NIHL.
2024-06-24 | GSE252285 | GEO
Project description:Presbycusis – age-related hearing loss – is the number one communicative disorder of our aged population. Here we analyzed gene expression for a set of GABA receptors in the cochlea of aging CBA mice using the Affymetrix GeneChip MOE430A. Functional phenotypic hearing measures distortion-product otoacoustic emission (DPOAE) amplitudes (four age groups) were made. The gene expression changes from RMA normalized microarray data (40 replicates) were first subjected to one-way ANOVA, and then linear regression was performed. In addition, the log signal ratio was converted to fold change, and selected gene expression changes were confirmed by relative real-time PCR. Major findings: expression of GABA-A receptor subunit 6was upregulated with age and hearing loss, whereas subunit 1 was repressed. In addition, GABA-A receptor associated protein like-1 and GABA-A receptor associated protein like-2 were strongly downregulated with age and hearing impairment. Lastly, gene expression measures were correlated with pathway/network relationships relevant to the inner ear using Pathway Architect, to identify key pathways consistent with the gene expression changes observed. In the study of expression changes GABA receptors in the in cochlea of young adult and aging presbycusis mice total of forty chips were used. The normal aging mice were in four groups young adults controls with good hearing (8 mice, 8 MOE430A GeneChips), Middle aged group with good hearing ( 17 mice, 17 MOE430A GeneChips), Mild Presbycusis (old) with limited hearing loss (9 mice, 9 MOE430A GeneChips) and Severe Presbycusis (old) (6 mice, 6 MOE430A GeneChips). Each Mice cochlea to each GeneChips, Samples was not pooled. The hearing potential evidence of each mouse is accompanied with each mice DPOAE amplitude.
2013-08-06 | E-GEOD-49543 | biostudies-arrayexpress
Project description:Age-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a meta-analysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 323,978) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5e-8), of which 30 have not been reported previously at genome-wide significance. We interpreted these loci in the context of newly generated ATAC-seq and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were enriched for expression in cochlear epithelial and non-epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in sensory epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type non-specific regulatory regions. Epigenomic and statistical fine-mapping most strongly supported 50 putative risk genes. Of these, at least 45 were expressed in mouse cochlea and 15 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.
2020-08-01 | GSE135737 | GEO