Transcriptional profiling reveals running promotes cerebrovascular remodeling in young but not midlife mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA549482 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9320620_1.fastq.gz | Fastqsanger.gz | |||
| SRR9320620_2.fastq.gz | Fastqsanger.gz | |||
| SRR9320630_1.fastq.gz | Fastqsanger.gz | |||
| SRR9320630_2.fastq.gz | Fastqsanger.gz | |||
| SRR9320640_1.fastq.gz | Fastqsanger.gz |
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Project description:We report that running at a young age showed ECM-related changes as well as angiogenesis-related pathways. Midlife running did not show this same affect.
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Project description:BACKGROUND:The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood. RESULTS:To better understand the effects of exercise, we preformed transcriptional profiling on young (1-2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells. CONCLUSIONS:Taken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.
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Project description:The Apolipoprotein E4 (ApoE4) allele is one of the strongest risk factors for late-onset Alzheimer’s disease (AD) and is associated with a breakdown of the blood-brain barrier and vascular dysfunction (Nation et al 2019; Liu and Bu 2022). Importantly, these vascular pathologies are exacerbated when APOE4 is coexpressed with familial mutations in APP or components of the γ-secretase complex (Montagne and Zlokovic 2021), suggesting that the interactions between APOE4 and AD mutations can drive progression of the disease. However, most studies have been done in aging animals and few look at the impact of APOE4 expression in young animals and how that potentially contributes toward late-stage disease susceptibility. Here, we examined the potential functional interaction between APP mutations and ApoE4 in the progression of AD pathophysiology by comparing the hippocampal transcriptomes of 3-month-old female mice of 4 different genotypes: AppNL-G-F/NL-G-F , which harbours three knock-in mutations in the humanised Aβ region of APP (APP-TKI; Saito et al., 2014), mice with a single allele of human ApoE4 knocked-in, ApoE4+/wt (ApoE4), crosses of these two mouse lines, to create AppNL-G-F/NL-G-F;Apoe4+/wt (double-mutant or DM) mice, and wild-type (WT) mice that served as controls. RNAseq revealed nascent microglial activation signatures in both APP-TKI and double mutant datasets, as well as subtle but significant differences between APP-TKI and double mutant in expression of a subset of vascular remodeling genes.
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Project description:The aging global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of interventions such as physical activity. Therefore, our aims were to 1) examine the impact of aging and exercise training on cerebrovascular function, and 2) to characterize age- and exercise training-related changes in the hippocampus transcriptome. Methods: Young and old male rats were randomized to a sedentary condition or exercise training for 10 weeks. In the first protocol, cerebral arteries were isolated to test vasomotor reactivity, quantify gene/protein expression, and to assess nitric oxide production. In the second protocol, anhedonia was assessed and hippocampal tissue collected for RNA-sequencing. Bioinformatic analyses (i.e., protein-protein interaction mapping) were performed. Results: Aging impaired endothelium-dependent vasoreactivity in the posterior communicating artery (PCoA), with a shift from endothelial NOS- to neuronal NOS-mediated vasorelaxation, and alterations in oxidative stress production. In support, PCoA superoxide-mediated vasoreactivity and nNOS-mediated production of NO increased with age. Exercise enhanced vasodilation in young rats, but results suggested reduced cerebrovascular plasticity in older animals. In the second protocol, exercise training attenuated the age-related increase in anhedonia behavior. Hippocampal RNA-sequencing revealed altered inflammatory and oxidative stress pathways with aging that were mitigated by exercise training. Conclusions: Our findings underscore the complex interplay between vascular/neuronal factors in the aging brain. Furthermore, these findings highlight the therapeutic potential of exercise in mitigating the adverse effects of aging on cerebral health
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Project description:Using Affymetrix GeneChip® Rat Genome 230 2.0 Array chip to screen the effect of Uphill and Downhill treadmill exercise on the key genes that affect bone mass in the peripheral blood mononuclear cells (PBMCs) of young male rats. Thirty-six male Sprague-Dawley rats were randomly assigned to a control group and both running groups of uphill and downhill (n = 12). Bone mineral density (BMD), bone mineral content (BMC) and bone microstructure of the femur were measured. PBMCs were extracted and the gene expression profile of mRNA detected.Gene Ontology and KEGG pathway analysis were used.The results showed exercise mainly activated the biological processes and cellular pathways involved in immune, inflammation and osteoclast differentiation.
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Project description:Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.
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Project description:Currently, the mechanisms behind the anti-aging effects of exercise are not understood. The presented study conducted a microarray on hippocampal samples from adult (3.5 month-old) and aged (18 month-old) male BALB/c mice that were individually housed with or without running wheels for 8 weeks. Results showed that aging altered genes related to chromatin remodeling, cell growth, immune activity, and synapse organization compared to adult mice. Exercise was found to modulate many of the genes altered by aging, but in the opposite direction. For example, wheel running increased expression of genes related to cell growth and attenuated expression of genes involved in immune function and chromatin remodeling. Collectively, findings show that even late-onset exercise may attenuate age-related changes in gene expression and identifies possible pathways through which exercise may exert its beneficial effects. In total 20 samples (4 aged exercise, 4 aged sedentary, 6 adult exercise, and 6 adult sedentary) plus 4 technical replicates (24 total) were analyzed.
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