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P1‐244: THE EFFECT OF SIRTUIN 3 ON TAU ACETYLATION IN ALZHEIMER'S DISEASE
Author(s) -
Yin Junxiang,
Han Pengcheng,
Beach Thomas G.,
Serrano Geidy E.,
Song Melissa,
Nielsen Megan,
Liang Winnie,
Caselli Richard J.,
Shi Jiong
Publication year - 2018
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.2018.06.249
Subject(s) - sirt3 , sirtuin , pathogenesis , neocortex , neuroprotection , tau protein , neuroscience , oxidative stress , pathological , alzheimer's disease , disease , senescence , medicine , endocrinology , psychology , pathology , chemistry , acetylation , biochemistry , gene
Background:Proteomic studies have identified many potential proteins associated with early diagnosis, differential diagnosis, prognosis and therapeutic response in diverse diseases. Recent proteomic analysis of Alzheimer’s disease (AD) plaques has identified a novel amyloid associated protein, secernin-1, which is a 50 kDa cytosolic protein (Acta Neuropathol 133: 933-954, 2017). Secernin-1 is known to regulate exocytosis in mast cells and increases both the extent of secretion and the sensitivity of mast cells to stimulation with calcium. It has been identified as a novel immunotherapy target for gastric cancer and a novel marker for prognosis in colorectal cancer. It is highly expressed in brain tissue and has dipeptidase activity. However, secernin-1 had not been previously known to be associated with neurodegenerative disorders.Methods: The presence of neuritic amyloid plaques and intracellular neurofibrillary tangles are hallmarksofADHowever the soluble oligomersof amyloid beta (Ab) and hyperphosphorylated tau are thought to be the major toxic species in AD. To determine the potential role of secernin-1 in AD neurodegeneration we initially performed in vitro binding experiments of human secernin-1 to theAbpeptide and to recombinant human Tau-His tag. These two AD proteins were polymerized by glutaraldehyde treatment to form stable oligomers. Binding was assessed by western blot analysis with mouse monoclonal antibodies to Ab (6E10, epitope residues 1-16; 4G8, epitope residues 17-24), Tau and rabbit polyclonal antiHuman secernin-1.Results:Surprisingly, the anti-secernin-1 antibody immunolabeled oligomers of Ab and tau at approximately their original molecular weight. There were no discrete higher molecular weight positive bands detected by any antibody that would correspond to a complex of Ab or tau oligomer and intact secernin-1. Therefore only a small fragment of secernin-1 may be complexedwith Ab and Tau oligomers. These complexes are being processed and analyzed by label-free quantitative LC–MS/MS analysis. Experiments with AD brain tissue extracts of Ab and tau oligomers are in progress. Conclusions: This secernin-1 peptide may be a novel marker for detection, prognosis and therapeutic evaluation in Alzheimer’s disease.