Project description:Metagenomics analysis reveals co-infection of fungi and bacteria isolated from different regions of brain tissue from elderly persons and patients with Alzheimer's disease.
Project description:We isolated highly purified CD8+CD28+ and CD8+CD28- T cell populations from healthy young and elderly persons for gene expression profiling using Affymetrix oligonucleotide microarrays. We demonstrate that the gene expression profile of CD8+CD28- T cells is very similar in young and elderly persons. In contrast, CD8+CD28+ in elderly differ from CD8+CD28+ in young persons. Hierarchical clustering revealed that CD8+CD28+ in elderly are located between CD8+CD28+ in young and CD8?CD28- (young and old) T cells regarding their differentiation state. Our study demonstrates a dichotomy of gene expression levels between CD8+CD28+ T cells in young and elderly persons but a similarity between CD8+CD28- T cells in young and elderly persons. As CD8+CD28+ T cells from elderly and young persons are distinct due to a different composition of the population, these results suggest that the gene expression profile does not depend on chronological age but depends on the differentiation state of the individual cell types.
Project description:Alzheimer's disease (AD) is a neurodegenerative disease, the most common cause of dementia in elderly persons. Accumulation of amyloid plaques in the brain is a characteristic of AD. The requirements for a biomarker include the ability to measure a pathologic process, predict outcome, distinguish disease or measure a pharmacological response to a drug treatment or therapeutic intervention. However, there are no reliable blood based biomarkers for AD. Serum-based protein measurement is a routine practice for biomarkers in human disease, but comprehensive profiling of serum proteome is often masked by the twenty most abundant proteins and impacted by large dynamic range. The commonly used depletion method can alleviate the challenge but introduce additional experimental variation. Here we present a deep analysis of un-depleted human serum proteome by combining 11-plex TMT labeling, exhaustive 2D liquid chromatography fractionation, and high resolution tandem mass spectrometry. This platform is capable of identifying 4,500 protein components, covering 6 orders of dynamic range, representing one of the deepest serum proteome datasets. Finally, a subset of proteins, show statistically significant difference between AD and control samples, which may serve as biomarker candidates.
Project description:Alzheimer's disease (AD) is a neurodegenerative disease, the most common cause of dementia in elderly persons. Accumulation of amyloid plaques in the brain is a characteristic of AD. The requirements for a biomarker include the ability to measure a pathologic process, predict outcome, distinguish disease or measure a pharmacological response to a drug treatment or therapeutic intervention. However, there are no reliable blood based biomarkers for AD. CSF-based protein measurement can be used as a practice for biomarkers in human disease, but comprehensive profiling of Mouse CSF proteome is often masked by the twenty most abundant proteins and impacted by large dynamic range. The commonly used depletion method can alleviate the challenge but introduce additional experimental variation. Here we present a deep analysis of un-depleted CSF proteome by combining 11-plex TMT labeling, exhaustive 2D liquid chromatography fractionation, and high resolution tandem mass spectrometry. This platform is capable of identifying 1056 protein components, covering 6 orders of dynamic range, representing one of the proteome datasets. Finally, a subset of proteins, show statistically significant difference between AD and control samples, which may serve as biomarker candidates for the AD when further correlation can be drawn from the human proteome.
Project description:We have performed methylation microarray analysis of two types of dementia, Alzheimer's disease (AD) and frontotemporal dementia (FTD), using two kind of samples, frozen brain tissue and lymphoblastoid cell lines.
Project description:Alzheimer's disease (AD) is the most common type of dementia. Extracellular amyloid β (Aβ) plaques and intracellular Tau-containing neurofibrillary tangles are major AD lesions that identify Alzheimer’s pathology and to neuronal loss. However, given that these structures are also seen in cognitively normal persons (healthy controls, HC) and in persons who have mild cognitive impairment (MCI), extensive efforts have been undertaken to identify other diagnostic or prognostic indicators. Here, we characterized the RNA contents of extracellular vesicles (EVs) in the plasma of age-matched individuals who are healthy or have MCI or AD. Using RNA sequencing analysis, we found that mitochondrial (mt)RNAs, including MT-ND1 through MT-ND6 and other protein-coding and noncoding mtRNAs, were strikingly elevated in MCI- and AD-associated plasma EVs compared with healthy control EVs. In cultured cells derived from astrocytes, microglia, and neurons, exposure to the toxic conditions in the AD environment (Aβ fibers and H2O2), EVs contained mitochondrial structures (as detected by electron microscopy) as well as mitochondrial RNAs. We propose that in the MCI and AD brain environment, toxicity causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs, and further propose that mitochondrial RNAs in plasma EVs are robust diagnostic and prognostic markers in AD.
Project description:Recently, the bone marrow (BM) has been shown to play a key role in regulating the survival and function of memory T cells. However, the impact of aging on these processes has not yet been studied. We demonstrate that the number of CD4+ and CD8+ T cells in the BM is maintained during aging. However, the composition of the T cell pool in the aged BM is altered with a decline of naïve and an increase in effector-memory T cells. In contrast to the peripheral blood (PB), a highly activated CD8+CD28– T cell population, which lacks the late differentiation marker CD57, accumulates in the BM of elderly persons. IL-6 and IL-15, which are both increased in the aged BM, efficiently induce the activation, proliferation and differentiation of CD8+ T cell in vitro, highlighting a role of these cytokines in the age-dependent accumulation of highly activated CD8+CD28– T cells in the BM. Yet, these age-related changes do not impair the maintenance of a high number of polyfunctional memory CD4+ and CD8+ T cells in the BM of elderly persons. In summary, aging leads to the accumulation of a highly activated CD8+CD28– T cell population in the BM, which is driven by the age-related increase of IL-6 and IL-15. Despite these changes, the aged BM is a rich source of polyfunctional memory T cells and may thus represent an important line of defense to fight recurrent infections in old age. A total of 4 samples (bone marrow mononuclear cells) were analyzed (2 young and 2 elderly persons)
Project description:We have performed gene expression microarray analysis of two types of dementia, Alzheimer's disease (AD) and frontotemporal dementia (FTD), using two kind of samples, frozen brain tissue and lymphoblastoid cell lines.
Project description:We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We now have analyzed additional samples with a confirmed pathologic diagnosis of late onset Alzheimer's disease (LOAD, final n=187 controls, 176 cases). Nine percent of the cortical transcripts we analyzed had expression profiles correlated with their genotypes in the combined cohort and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power to find risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease. see DOI:10.1016/j.ajhg.2009.03.011 for further details and complete author list.
Project description:Here we provide a proteomic resource comprising nine functionally distinct sections from three individuals clinically diagnosed with Alzheimer's disease, across a spectrum of disease progression. Using state-of-the-art mass spectrometry, we identify a core brain proteome that exhibits only small variance in expression, accompanied by a group of proteins that are highly differentially expressed in individual sections and broader regions. AD affected tissue exhibited slightly elevated levels of tau protein with similar relative expression to factors associated with the AD pathology. Substantial differences were identified between previous proteomic studies of mature adult brains and our aged cohort. Our findings suggest considerable value in examining specifically the brain proteome of aged human populations, with the goal of understanding ways in which neurological changes occur past full maturity. This resource can serve as a guide, as well as a point of reference for how specific regions of the brain are affected by aging.