Abstract
Background: Alzheimer's disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases. However, validated peripheral biomarkers for AD diagnosis are not available up to present. In this study, we adopted a new strategy of combination of computational prediction and experimental validation to identify blood protein biomarkers for AD.Methods: First, we collected tissue-based gene expression data of AD patients and healthy controls from GEO database. Second, we analyzed these data and identified differentially expressed genes for AD. Third, we applied a blood-secretory protein prediction program on these genes and predicted AD-related proteins in blood. Finally, we collected blood samples of AD patients and healthy controls to validate the potential AD biomarkers by using ELISA experiments and Western blot analyses.Results: A total of 2754 genes were identified to express differentially in brain tissues of AD, among which 296 genes were predicted to encode AD-related blood-secretory proteins. After careful analysis and literature survey on these predicted blood-secretory proteins, ten proteins were considered as potential AD biomarkers, five of which were experimentally verified with significant change in blood samples of AD vs. controls by ELISA, including GSN, BDNF, TIMP1, VLDLR, and APLP2. ROC analyses showed that VLDLR and TIMP1 had excellent performance in distinguishing AD patients from controls (area under the curve, AUC = 0.932 and 0.903, respectively). Further validation of VLDLR and TIMP1 by Western blot analyses has confirmed the results obtained in ELISA experiments.Conclusion: VLDLR and TIMP1 had better discriminative abilities between ADs and controls, and might serve as potential blood biomarkers for AD. To our knowledge, this is the first time to identify blood protein biomarkers for AD through combination of computational prediction and experimental validation. In addition, VLDLR was first reported here as potential blood protein biomarker for AD. Thus, our findings might provide important information for AD diagnosis and therapies.
Highlights
Alzheimer’s disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases [1]
Pathway enrichment analysis was conducted on these genes and showed that focal adhesion, TGFβ signaling pathway, and MAPK signaling pathway were significantly enriched by up-regulated genes, and synapse transmission, neuronal system, and calcium signaling pathway were significantly enriched by down-regulated genes [complete list shown in our previous study [27]]
GO enrichment analysis on the predicted blood-secretory proteins suggested that they were associated with AD and might act as candidate protein biomarkers of AD in blood
Summary
Alzheimer’s disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases [1] This disease is pathologically characterized with extracellular senile plaques (amyloid-β, Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are the prime suspects in damaging and killing nerve cells [2]. Blood contains large number of disease-associated proteins and its obtaining is non-invasive, it becomes a good source for discovery of AD biomarkers. Alzheimer’s disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases.
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