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O1‐01‐01: INTEGRATIVE PROTEOMICS LINKS CEREBROSPINAL FLUID BIOMARKERS TO PATHOLOGICAL NETWORKS IN THE ALZHEIMER'S DISEASE BRAIN
Author(s) -
Ping Lingyan,
Higginbotham Lenora A.,
Dammer Eric B.,
Duong Duc,
Zhou Maotian,
Wingo Thomas S.,
Johnson Erik C.B.,
Lah James J.,
Levey Allan I.,
Seyfried Nicholas T.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4517
Subject(s) - cerebrospinal fluid , proteome , proteomics , biomarker , tandem mass tag , pathological , biomarker discovery , neurodegeneration , disease , isobaric labeling , pathophysiology , alzheimer's disease , pathology , medicine , quantitative proteomics , neuroscience , bioinformatics , biology , biochemistry , gene
Background: There is a need for novel biomarkers of Alzheimer’s disease (AD) that broadly serve as accurate indicators of the underlying pathophysiological processes occurring throughout disease. Thus, biomarker discovery should focus on identifying not only targets that are easily accessible and reliably measured, but also those with clear associations to the most critical mechanisms driving neurodegeneration. To achieve this goal, we used an unbiased proteomic approach to quantify protein levels in AD cerebrospinal fluid (CSF) and linked these changes to network-based pathophysiology in diseased brains.Methods: Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) we comparatively analyzed the CSF proteomes from 40 samples, including 20 cognitively normal individuals (avg. MoCA1⁄426.7) and 20 subjects with clinical diagnoses of AD (avg. MoCA1⁄413.8). AD individuals demonstrated low amyloid (223.4 pg/mL) and high tau (143.5 pg/ mL) levels compared to controls (540.4 pg/mL and 70.2 pg/mL, respectively) as measured by ELISA. The top 14 most abundant proteins in each CSF samplewere depleted prior to proteolytic digestion and labeling with isobaric tandem-mass tags (TMT). Differential expression analysis resolved CSF proteins increased or decreased in AD. CSF protein biomarkers of AD were then mapped to TMT proteomic networks generated from control, AD, asymptomatic AD (AsymAD), and Parkinson’s disease (PD) postmortem brain tissue (n1⁄467 tissues). Results: CSF proteomic analysis revealed a total of 2,875 proteins across all 40 samples, of which w70% were also measured in our brain proteome. Network analysis of the brain proteome identified a total of 8,817 proteins organized into 44 modules. Fifteen brain modules had a significant overlap with proteins identified in CSF. Synaptic and mitochondrial proteins mapping to three modules enriched with neuronal markers showed overall decreased levels in the AD brain, but increased levels in AD CSF. Conversely, Tau and microglial proteins mapping to modules associated with neuroinflammation (n1⁄43) showed increased abundance in both the brain and CSF. Expression levels of thesemicroglial modules in AsymAD brains indicated that these changes may start early in disease. Conclusions: These results provide a framework for identifying CSF markers highly reflective of underlying disease pathophysiology that could potentially serve as therapeutic targets.