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O4‐12‐03: Brain phosphoproteome network analysis discriminates Alzheimer's disease from other tauopathies
Author(s) -
Dammer Eric B.,
Ren Rujing,
Duong Duc M.,
Lee Andrew K.,
Gearing Marla,
Lah James J.,
Levey Allan I.,
Seyfried Nicholas T.
Publication year - 2015
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.2015.07.415
Subject(s) - progressive supranuclear palsy , tauopathy , phosphorylation , chemistry , frontotemporal dementia , phosphopeptide , tau protein , corticobasal degeneration , gene isoform , threonine , neurodegeneration , biochemistry , neuroscience , alzheimer's disease , biology , serine , atrophy , disease , pathology , dementia , medicine , genetics , gene
Background: Neurofibrillary tangles (NFT), scaffolds of highly phosphorylated tau protein, are a core pathological feature of Alzheimer’s disease (AD) and several other neurodegenerative diseases collectively termed tauopathies, which include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and certain frontotemporal dementias. There are six isoforms of human tau in brain and over 40 serine (S), threonine (T), and tyrosine (Y) tau phosphorylation sites have been identified. Progressive site-specific phosphorylation of tau at specific S/T/Y sites is hypothesized to cause both functional deficits as well as gain-of-function toxicity that ultimately lead to NFT formation, synaptic loss, and cognitive dysfunction. Despite being clinically distinct diseases it remains unclear whether site-specific tau phosphorylation differs between AD and other tauopathies. Methods:Following tissue homogenization and in-solution trypsin digestion, phosphopeptides were enriched by an optimized immobilized metal affinity chromatography (IMAC) protocol using ferric chloride from individual AD, tauopathy (CBD and PSP) and age-matched control postmortem human brain tissues (n1⁄4 7 per group). Liquid chromatographytandem mass spectrometry (LC-MS/MS) was subsequently employed to identify and quantify tau phosphopeptides among other globally enriched phosphopeptides from each tissue sample. Accurate peptide mass and retention time was used to derive signal intensity for every phosphopeptide across LC-MS/MS runs for each case. Results: In total, 77 tau phosphopeptides representing 32 S/T/Y sites were analyzed by WeiGhted Correlation Network Analysis (WGCNA) to delineate tau phosphosites co-enriched in a disease specific manner. Correlated intensity with other phosphopeptides from the same samples, and the phosphorylation pattern of tau itself each suggest that mechanisms underlying site-specific tau phosphorylation differ between AD and other tauopathies. Conclusions:This study highlights the utility of mass spectrometry based proteomics to quantify tau and other brain phosphosignatures with potential to discriminate AD from other tauopathies.