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Quantitative proteomic profiling of brain in Alzheimer’s disease

ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia and the number of AD patients is expected to increase as human life expectancy improves. The deposition of β-amyloid protein (Aβ) in the extracellular matrix and neurofibrillary tangles intracellularly are pathologic hallmarks. Since the precise pathophysiology of AD has not been clearly elucidated yet, effective treatment is not available. Thus the development of valid AD biomarkers is imperative for early diagnosis and for monitoring disease progression and therapeutic responses.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey, M.D, Ph.D.

PROVIDER: PXD010560 | Pride | 2022-04-01

REPOSITORIES: Pride

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			Action	DRS
	ADTMT10R1.raw	Raw
	ADTMT10R2.raw	Raw
	ADTMT11R1.raw	Raw
	ADTMT11R2.raw	Raw
	ADTMT12R1.raw	Raw

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Publications

Quantitative proteomic analysis of the frontal cortex in Alzheimer's disease.

Sathe Gajanan G Albert Marilyn M Darrow Jacqueline J Saito Atsushi A Troncoso Juan J Pandey Akhilesh A Moghekar Abhay A

Journal of neurochemistry 20200722 6

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by intracellular formation of neurofibrillary tangles and extracellular deposition of β-amyloid protein (Aβ) in the extracellular matrix. The pathogenesis of AD has not yet been fully elucidated and little is known about global alterations in the brain proteome that are related to AD. To identify and quantify such AD-related changes in the brain, we employed a tandem mass tags approach coupled to high-resolution mass s ...[more]

PMID: 32614981

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Quantitative proteomic profiling of cerebrospinal fluid to identify candidate biomarkers for Alzheimer’s disease

Project description:Alzheimer's disease (AD) is the most prevalent form of dementia and the number of AD patients is expected to increase as human life expectancy improves. The deposition of β-amyloid protein (Aβ) in the extracellular matrix and neurofibrillary tangles intracellularly are pathologic hallmarks of AD in the brain. However, there are no reliable circulating biomarkers for accurate diagnosis of AD. In this study, we employed high-resolution mass spectrometry and tandem mass tags (TMT) to identify candidate biomarkers for Alzheimer’s disease. A subset of the identified candidates was validated using multiplexed targeted PRM-LC-MS/MS analysis in an independent cohort.

2019-01-10 | PXD008098 | Pride

Phosphoproteomic analysis of brain form Alzheimer’s disease

Project description:Alzheimer's disease (AD), the most common neurodegenerative disorder caused by neuronal loss which results in memory loss. Formation of neurofibrillary tangles composed of abnormal hyper phosphorylation of tau protein is one of the major pathological hallmarks for AD. Several neurodegenerative disorders including AD are associated with abnormal protein phosphorylation events.

2021-09-08 | PXD010807 | Pride

The Periodontal Pathogen Fusobacterium nucleatum Exacerbates Alzheimer’s Pathogenesis via Specific Pathways

Project description:Alzheimer’s disease (AD) is the most common form of dementia in older adults and has a devastating impact on the patient’s quality of life, which creates a significant socio-economic burden for the affected individuals and their families. In recent years, studies have identified a relationship between periodontitis and AD. Periodontitis is an infectious/inflammatory disease that destroys the supporting periodontal structure leading to tooth loss. Dysbiosis of the oral microbiome plays a significant role in the onset and development of periodontitis exhibiting a shift to overgrowth of pathobionts in the normal microflora with increasing local inflammation. Fusobacterium nucleatum is a common pathogen that significantly overgrows in periodontitis and has also been linked to various systemic diseases. Earlier studies have reported that antibodies to F. nucleatum can be detected in the serum of patients with AD or cognitive impairment, but a causal relationship and a plausible mechanism linking the two diseases have not been identified. In this study, we conducted both in vivo and in vitro experiments and found that F. nucleatum activates microglial cells causing morphological changes, accelerated proliferation and enhanced expression of TNF-α and IL-1β. In our in vivo experiments, we found that F. nucleatum-induced periodontitis resulted in the exacerbation of Alzheimer’s symptoms in 5XFAD mice including increased cognitive impairment, beta-amyloid accumulation and Tau protein phosphorylation in the mouse cerebrum. This study may suggest a possible link between a periodontal pathogen and AD and F. nucleatum could be a risk factor in the pathogenesis of AD. We are currently further identifying the pathways through which F. nucleatum modulates molecular elements in enhancing AD symptoms and signs.

2022-08-12 | PXD033147 | Pride

Molecular alterations elicited by chronic exposure to cigarette smoke in oral keratinocytes

Project description:Smoking is the leading cause of preventable death worldwide. It increases the risk for various diseases including respiratory diseases, vascular diseases and different cancers including lung, oral and bladder cancer. Despite being the leading cause of oral cancer, the molecular mechanisms resulting in malignancy upon cigarette smoke exposure are yet to be fully elucidated. It is crucial to note that disease development is observed upon chronic exposure to cigarette smoke, as opposed to a short-term exposure. Hence, we sought to investigate the effect of chronic smoke exposure on normal oral keratinocytes (OKF6/TERT1). We employed tandem mass tag-based quantitative proteomic and phosphoproteomic approaches to investigate the proteomic and signaling changes in OKF6/TERT1 cells chronically exposed to cigarette smoke compared to untreated cells. LC/MS2 analysis resulted in the quantification of 5,067 proteins among which expression of 360 proteins were found to be dysregulated in at least one replicate. Phosphoproteomic analysis revealed quantification of 3,647 phosphopeptides corresponding to 1,801 proteins. Majority of the dysregulated proteins were seen to be involved in cellular processes such as cell growth, cellular communication and energy metabolism. This study will aid in elucidating the effects of smoking in oral cancer and in the identification of potential candidates molecules which could serve as early detection biomarkers or therapeutic targets.

2018-03-05 | PXD007637 | Pride

Phosphoproteomic Analysis Suggests Compensatory Effects in the Piriform Cortex Region of the VX-Exposed Rat

Project description:To gain insight into the toxicity induced by VX, a mass spectrometry based phosphoproteomics approach was employed to understand the signaling modulated by VX toxicity in piriform cortex region of the rat brain. We have employed isobaric-based TMT labeling and titanium dioxide- based enrichment strategy to identify and quantify the changes that are modulated by VX. We observed a temporal association of changes in the phosphorylation status of proteins over a 24 hour time course in rats exposed to 1x LD50 VX, with the most notable changes by the first measured time point, 1 hour post exposure. These data fell into five main functional classes of proteins directly or indirectly influenced by changes in phosphorylation: 1) Ion channels/transporters, including ATPases, 2) Kinases/Phosphatases, 3) GTPases, 4) Structural related proteins, and 5) Transcriptional regulatory proteins. This study is the first quantitative phosphoproteomics analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain, and aid in the elucidation of novel molecular targets allowing for improved countermeasure development.

2015-01-07 | PXD001184 | Pride

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Project description:Degeneration of synapses in Alzheimer’s disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. Our analysis identified over 5,500 proteins in human synaptoneurosomes and highlighted disease and APOE-associated changes in multiple molecular pathways including a disruption of cellular and synaptic signalling, glial related protein changes important for neuroinflammatory neuron-glia interactions, and changes in proteins important for mitochondrial function in AD that differ with APOE genotype.

2020-05-26 | PXD013753 | Pride

Molecular alterations elicited by chronic exposure to cigarette smoke and chewing tobacco in oral keratinocytes

Project description:Tobacco is mainly consumed in two different forms (smoking and chewing) that vary in their composition and methods of intake. Despite being the leading cause of oral cancer, the molecular mechanisms resulting in malignancy upon tobacco exposure are yet to be fully elucidated. We therefore sought to compare the molecular alterations in oral keratinocytes exposed to smoke and chewing tobacco. OKF6/TERT1 cells were exposed to cigarette smoke condensate or chewing tobacco for progressively increasing durations (2, 4, 6 and 8 months). We employed a TMT-based quantitative proteomics approach to investigate the adverse effects of chronic cigarette smoke or chewing tobacco exposure in oral keratinocytes. LC/MS3 analysis resulted in the quantification of 5,342 proteins and 2,821 proteins in cigarette smoke and chewing tobacco exposed cells, respectively. Upstream regulator analysis indicates the involvement of distinct regulators in CSC exposed cells compared to STE exposed cells. In addition, exome sequencing revealed discrete genetic alterations in cells exposed to each insult. Current analysis defines a clear distinction in the molecular dysregulation in oral cells in response to different tobacco-based insults. Some of the proteins dysregulated in cigarette smoke or chewing tobacco exposed cells may serve as potential early detection biomarkers which could aid in stratification of patients based on tobacco usage history.

2019-11-08 | PXD007127 | Pride

PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40)

Project description:Gallbladder cancer (GBC) is associated with poor disease prognosis with a survival of less than 5 years in 90% the cases. This has been attributed to late presentation of the disease, lack of early diagnostic markers and limited efficiency of therapeutic interventions. Elucidation of the molecular events in GBC carcinogenesis can contribute in better management of the disease by aiding in identification of therapeutic targets. To identify the aberrantly activated signaling events in GBC, tandem mass tag-based quantitative phosphoproteomic analysis of five GBC cell lines based on the invasive property was carried out. Using a panel of five GBC cell lines, a total of 2,623 phosphosites from 1,343 proteins were identified. Of these, 55 phosphosites were hyperphosphorylated and 39 phosphosites were hypophosphorylated in both replicates and all the 4 invasive GBC cell lines. Proline-rich Akt substrate 40 kDa (PRAS40) was one of the proteins found to be hyperphosphorylated in all the invasive GBC cell lines. Tissue microarray-based immunohistochemical labeling of phospho-PRAS40 (T246) revealed moderate to strong staining in 77% of the primary gallbladder adenocarcinoma cases. Inhibition of PRAS40 phosphorylation using inhibitors of its upstream kinases, PIM1 and AKT resulted in a significant decrease in cell proliferation, colony forming and invasive ability of the GBC cells. Our findings support the role of PRAS40 phosphorylation in tumor cell survival and aggressiveness in GBC and suggest its potential as a therapeutic target for GBC.

2019-01-28 | PXD007946 | Pride

Cigarette smoke induces mitochondrial metabolic reprogramming in lung cells

Project description:Cigarette smoking remains the leading cause of non-small cell lung carcinoma. Studies involving acute exposure of smoke on lung cells revealed induction of pre- cancerous state in lung cells. Recently few studies have reported the chronic effect of cigarette smoke in inducing cellular transformation. Yet no systemic study has been performed to understand the molecular alterations in lung cells due to cigarette smoke. Hence it is both important and necessary to study the chronic effect of cigarette smoke in a temporal setting to understand the molecular alterations. In this study, we carried out TMT based proteomic profiling of lung cells which were exposed to cigarette smoke condensate (CSC) for upto 12 months. We identified 2621 proteins in total, of which 145, 114, 87, 169 and 671 proteins were differentially expressed (p<0.05, 1.5 fold) in 2nd, 4th, 6th, 8th and 12th month respectively. Pathway analysis revealed enrichment of xenobiotic metabolism signaling for the first 8 months of smoke treatment, where as continued exposure of smoke for 12 months revealed mitochondrial reprogramming in cells which includes dysregulation of oxidative phosphorylation machinery leading to enhanced reactive oxygen species and higher expression of enzymes involved in tricarboxylic acid cycle (TCA). In addition, chronic exposure of smoke led to overexpression of enzymes involved in glutamine metabolism, fatty acid degradation and lactate synthesis. This could possibly explain the availability of alternative source of carbon in TCA cycle apart from glycolytic pyruvate. Our data indicates that chronic exposure to cigarette smoke induces mitochondrial metabolic transformation in cells to support growth and survival.

2022-03-02 | PXD007108 | Pride

Ad-MyD88 infected bmDCs: Control vs. Ad-MyD88 infected

Project description:Transcriptional profiling of Bone-Marrow derived mouse Dendritic Cells (bmDCs) infected with Ad-MyD88 vs. Ad-GFP or mock infected Three-condition experiment, Ad-MyD88 vs. Ad-GFP vs. Mock infected cells. Biological replicates: 3 Ad-MyD88, 3 Ad-GFP, 3 mock, independently grown and harvested. One replicate per array.

2010-10-08 | E-GEOD-19006 | biostudies-arrayexpress

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