Dataset Information

Ultra Deep Mouse cerebrospinal fluid (CSF) profiling in Alzheimer’s disease

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Alzheimer's Disease 3

SUBMITTER: Kaushik Dey

LAB HEAD: Junmin Peng

PROVIDER: PXD018658 | Pride | 2021-09-09

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	Mouse_CSF_Fra_33.1.pepXML	Pepxml
	Mouse_CSF_Fra_33.mzXML	Mzxml
	Mouse_CSF_Fra_33.raw	Raw
	Mouse_CSF_Fra_34.1.pepXML	Pepxml
	Mouse_CSF_Fra_34.mzXML	Mzxml

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Publications

Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease.

Wang Hong H Dey Kaushik Kumar KK Chen Ping-Chung PC Li Yuxin Y Niu Mingming M Cho Ji-Hoon JH Wang Xusheng X Bai Bing B Jiao Yun Y Chepyala Surendhar Reddy SR Haroutunian Vahram V Zhang Bin B Beach Thomas G TG Peng Junmin J

Molecular neurodegeneration 20200725 1

<h4>Background</h4>Based on amyloid cascade and tau hypotheses, protein biomarkers of different Aβ and tau species in cerebrospinal fluid (CSF) and blood/plasma/serum have been examined to correlate with brain pathology. Recently, unbiased proteomic profiling of these human samples has been initiated to identify a large number of novel AD biomarker candidates, but it is challenging to define reliable candidates for subsequent large-scale validation.<h4>Methods</h4>We present a comprehensive stra ...[more]

PMID: 32711556

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Project description:s synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.