Project description:We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules. However, these changes do not localize to microglia, the major CNS immunocyte. Consistent with a neuronal role, there is a marked age-related increase in excitatory synapses over the cerebellum and hypothalamus. Functional imaging of these regions is consistent with age-related synaptic impairments. These studies suggest that aging reactivates a developmental program employed during embryogenesis where immune molecules guide synapse formation and pruning. Renewed activity in this program may disrupt excitatory neurotransmission, causing significant behavioral deficits. keywords: aging, C57BL/6, BALB, CBA, hypothalamus, cerebellum, striatum, frontal cortex
Project description:Aging is believed to be the result of alterations of protein expression and accumulation of changes in biomolecules. Although there are numerous reports demonstrating changes in protein expression in brain during aging, only few of them describe global changes in the protein level. Here, we present a deepest quantitative proteomic analysis of three brain regions, hippocampus, cortex and cerebellum, in mice aged 1 and 12 months, using the total protein approach technique. In all the brain regions, both in young and in middle-aged animals, we identified over 6,700 proteins. We found that although the total protein expression in middle-aged brain structures is practically unaffected by aging, there are significant differences between young adult and middle-aged mice in the expression of some receptors and signaling cascade proteins proven to be significant for learning and memory formation. Our analysis demonstrates that hippocampus is the most unstable structure during natural aging and that the first symptoms of weakening of neuronal plasticity may be observed on protein level in middle-aged animals.
Project description:We have used microarrays to analyze gene expression in Parkinson’s disease (PD). We used four different brain regions, including two that are relatively affected in PD (striatum and cortex) and two that are relatively spared (cerebellum and medulla). We show that while differences between brain regions are strong, expression profile differences between PD and controls are much more modest and that genome-wide significant differences are restricted to the striatum and cerebral cortex. RNA (aRNA) was generated from 500ng of total RNA from the medulla (n=15 control brains, n=14 PD brains), striatum (n=15 control brains, n = 15 PD brains), frontal cortex (n=15 control brains, n = 11 PD brains) and cerebellum (n = 14 control brains, n=15 PD brains).
Project description:Comparison of the gene expression profiles of adult human brain samples from frontal cortical regions, including samples from young, middle aged, normal aged, and AlzheimerM-bM-^@M-^Ys disease (AD) brains. Comparison of 12 young (<40yr), 9 middle aged (40-70yr), 16 normal aged (70-94yr), and 4 extremely aged (95-106yr)
Project description:Comparison of the gene expression profiles of adult human brain samples from frontal cortical regions, including samples from young, middle aged, normal aged.
Project description:By looking at the transcriptome of the hypothalamus, frontal cortex and striatum, we studied how the fine balance between the homeostatic and hedonic control of food intake can be influenced by diet
Project description:Recent studies show that acute injury to non-aged podocytes induces many similarities to healthy aged podocytes, such as decreased lifespan and health-span. Like healthy aged podocytes, injury to young mouse and human podocytes can induce a senescent phenotype. This begs the question if injury to young podocytes phenocopies a healthy middle-aged podocyte, and if the pathways underlying senescence and other injury responses overlap between injured young podocytes and healthy middle-aged podocytes. To address this knowledge gap we induced hypertension, a major cause of chronic kidney disease, in young mice (4m of age~20-year-old human) and in middle-aged mice (18m of age, ~55+ year old human) with deoxycorticosterone and high salt (DOCA) and compared outcomes to non-hypertensive healthy middle-aged mice. In both healthy middle-aged mice and in young mice with hypertension, the increase in age-related senescent genes p16 and p19, along with the stress-related senescent genes p21 and p53 were similar. Bulk RNA-sequencing of podocytes showed that the senescent associated secretory phenotype and individual genes from several aging gene sets were also similar between middle-aged mice and young mice with hypertension. Of the highest enriched Hallmark pathways in middle-aged podocytes, 95% were also enriched in young mice treated with DOCA. Gene set enrichment analysis of podocytes showed that 36 genes overlapped between middle-aged mice, and young and middle-aged mice given DOCA, while 119 genes identified were “DOCA-specific”. These results suggest that hypertension in young mice induces podocyte injury and an aging/senescent phenotype that is similar to the one of podocytes from healthy middle-aged mice.
Project description:The aging brain shows changes in microglial function, morphology, and phenotype, indicating chronic microglial activation. CX3CR1 is crucial for microglial chemotaxis, phagocytosis, and activation. However, its exact role in the aging brain is not well understood. In this study, we examined the expression of CX3CR1 in the brains of middle-aged mice (10 months old) and explored its functional implications by conducting proteomic profiling in CX3CR1-deficient mouse cerebrum. Proteomic analysis revealed an enrichment of differentially expressed proteins (DE-proteins) in the cerebrum of middle-aged mice in GO pathways such as “synapse”, “translation”, and “ribosome”. CX3CR1 deficiency affected protein levels in GO pathways such as “glutamatergic synapse” and “RNA splicing.” We also detected the proteomics in age-matched 5xFAD mice for comparison, since this mouse strain featured aberrant microglial activation and CX3CR1 upregulation in the hippocampus and frontal cortex. Our findings demonstrated that CX3CR1 was upregulated to maintain synaptic homeostasis probably through regulating microglial activation and phagocytosis in the brains of middle-aged mice. CX3CR1 may represent a promising therapeutic target for alleviating the effects of aging and preventing neurodegeneration.