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Ultra-sensitive detection of protein biomarkers for diagnosis of Alzheimer's disease.

ABSTRACT: Beta amyloid peptide, tau, and phosphorylated tau are well recognized as promising biomarkers for the diagnosis of Alzheimer's disease (AD). In this work, we developed a direct, versatile, and ultrasensitive multiplex assay for the quantification of trace amounts of these protein biomarkers for AD in different types of biological fluids including cerebrospinal fluid, serum, saliva, and urine. The detection assay is based on the immunoreaction between the target proteins and their corresponding pair of antibodies followed by fluorescence labelling with a newly developed indolium-based turn-on fluorophore, namely SIM. SIM was tailor-made as a reporter to provide a high signal-to-noise ratio for the detection assay. An exceptionally low limit of detection down to the femto-molar level was achieved in this assay with minute consumption of the sample. This versatile detection assay is capable of reliably quantifying not only the target proteins simultaneously from a CSF sample in an hour but also trace amounts of protein biomarkers in saliva and urine. This assay has a high potential to serve as a practical tool for the diagnosis of AD.

SUBMITTER: Chan HN

PROVIDER: S-EPMC6094176 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Ultra-sensitive detection of protein biomarkers for diagnosis of Alzheimer's disease.

Chan Hei-Nga HN Xu Di D Ho See-Lok SL Wong Man Shing MS Li Hung-Wing HW

Chemical science 20170324 5

Beta amyloid peptide, tau, and phosphorylated tau are well recognized as promising biomarkers for the diagnosis of Alzheimer's disease (AD). In this work, we developed a direct, versatile, and ultrasensitive multiplex assay for the quantification of trace amounts of these protein biomarkers for AD in different types of biological fluids including cerebrospinal fluid, serum, saliva, and urine. The detection assay is based on the immunoreaction between the target proteins and their corresponding p ...[more]

PMID: 30155210

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Project description:Many factors are involved in Alzheimer's disease (AD) pathology including tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress, and inflammation. The markers of these pathological processes in cerebral spinal fluid are used currently for AD diagnosis. However, peripheral biomarkers are the need of the hour for large population screening for AD. The main objective of the present study is to evaluate the peripheral levels of redox markers, lipid peroxidation (LPO) indicators, and pathological markers in AD patients. Blood was collected from AD patients (n = 45), controls (n = 45), and analyzed for pathological markers of AD including Aβ42 and tau, LPO, and redox indicators. Plasma Aβ42 was significantly (P < 0.001) elevated while total tau was decreased in AD compared to controls. Hydroxynonenal (HNE) and malondialdehyde (MDA) were higher (P < 0.001) in AD patients pointing the enhanced LPO in AD pathology. Receiver operating characteristic curve (ROC) analysis indicated that HNE is a better indicator of LPO compared to MDA. Plasma glutathione (GSH) level was significantly (P < 0.001) low while oxidized glutathione (GSSG) level was higher (P < 0.001) in AD patients with corresponding decrease in GSH/GSSG ratio (P < 0.001). ROC analysis indicated that GSH/GSSG ratio can be used as reliable indicator for redox imbalance in AD with a cutoff value of <8.73 (sensitivity 91.1%, specificity 97.8%). Correlation analysis revealed a positive correlation for both HNE and MDA with Aβ42 and a negative correlation with total tau. Negative correlation was observed between GSH/GSSG ratio and LPO markers. While oxidative stress has been implicated in pathology of various neurodegenerative disorders, the present study pinpoints the direct link between LPO and Aβ production in plasma of AD patients. Normally, at low amyloid concentration in body fluids, this peptide shown to function as a strong metal chelating antioxidant. However, when the Aβ production enhanced as in AD, through gain of functional transformation, Aβ evolves into prooxidant, thereby enhancing oxidative stress and LPO. Altered redox status with enhanced LPO observed in AD blood could contribute to the oxidation and S-glutathionylation proteins, which has to be addressed in future studies.

Project description:Alzheimer's disease (AD), a chronic neurodegenerative disease associated with the loss of neurons in the brain, is the most pervasive type of dementia; 47 million people are affected, and the number is expected to increase to more than 131 million by 2050, according to Alzheimer's Disease International. Both early diagnosis and continuous monitoring are crucial for early intervention, symptomatic treatment, monitoring of the efficacy of intervention and improved patient function. Beta-amyloid peptide, tau, and phosphorylated tau are useful for screening and diagnosis; meanwhile, simultaneous assessment of multiple biomarkers is of paramount importance for accurate disease diagnosis. Methods: Herein, we report a direct, inexpensive and ultrasensitive aptamer-based multiplex assay for the quantification of trace amounts of AD biomarkers in both human serum and cerebrospinal fluid (CSF) samples. In this newly developed assay, molecular recognition of an antibody-aptamer pair provides high specificity in target detection, and the use of a DNA amplification strategy affords high sensitivity, allowing quantification of AD biomarkers in both biological fluids in 1.5 h with only a diminutive amount of the sample consumed. A tailor-made turn-on fluorophore, namely, SPOH, was employed to label the antibody-aptamer hybrids and provide a strong fluorescence signal, which was then detected with a total internal reflection fluorescence microscopy electron-multiplying charge-coupled device (TIRFM-EMCCD) imaging system. The simultaneous detection of biomarkers was achieved by a direct shape-coded method in which the nanoplatforms can be distinguished from one another by their morphologies. Results: This assay demonstrated a lower detection limit (in the femtomolar range) for AD biomarkers than the previously reported antibody-antibody method. Conclusion: The developed assay holds tremendous clinical potential for early diagnosis of AD and monitoring of its progression.

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Ultra-sensitive detection of protein biomarkers for diagnosis of Alzheimer's disease.

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Ultra-sensitive detection of protein biomarkers for diagnosis of Alzheimer's disease.

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