Deep serum proteomics detects sex-influenced signature in a murine model of Alzheimer's disease

ABSTRACT: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is categorized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. By using mouse models and performing In-depth analysis of the serum proteome has the potential to identify biomarkers that would allow for both early disease detection and measurement of disease progression. Here, we present an ultra-deep, multiplexed, undepleted mouse serum proteome by combining TMT pro-16-plex tandem-mass-tag (TMT)-based labeling, exhaustive two-dimensional liquid chromatography (LC/LC) fractionation, and sample concatenation based on the peptide concentration intensity (low, medium, and high) coupled with high resolution tandem mass spectrometry (MS/MS). We optimized a platform capable of analyzing 4100 protein components (3788 genes), covering a dynamic range of at least 6 orders of magnitude, representing one of the deepest serum proteome analyses by extensive fractionation and concatenation to date. Differential expression (DE) analysis between WT and 5xFAD mouse models showed essentially no protein changes except Lcn11. Interesting, our method detected 65 sex-dependent DE proteins with statistical significance (FDR < 0.05), including some earlier reported molecules related towards AD disease progression Serpina3h, Serpina3c, A1bg, Ncam2, Fgl1, Hamp, Kif15, Man2b2, Egfr, Prl etc, had adequate sensitivity and reproducibility to detect sex-dependent differentially expressed proteins in disease-related pathways. Hence, our newly developed protocol revealed alterations in key sex-related proteins that can be differentiated in serum analysis, both known and novel, which may be relevant to the development of assays for the monitoring and/or treatment various diseases.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Serum

DISEASE(S): Alzheimer&apos;s Disease

SUBMITTER: Kaushik Kumar Dey  

LAB HEAD: Junmin Peng

PROVIDER: PXD044306 | Pride | 2024-05-21

REPOSITORIES: Pride