Dataset Information

Increased levels of antigen-bound ?-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients.

ABSTRACT: Recent studies have suggested a protective role of physiological ?-amyloid autoantibodies (A?-autoantibodies) in Alzheimer's disease (AD). However, the determination of both free and dissociated A?-autoantibodies in serum hitherto has yielded inconsistent results regarding their function and possible biomarker value. Here we report the application of a new sandwich enzyme-linked immunosorbent assay (ELISA) for the determination of antigen-bound A?-autoantibodies (intact A?-IgG immune complexes) in serum and cerebrospinal fluid (CSF) of a total number of 112 AD patients and age- and gender-matched control subjects. Both serum and CSF levels of A?-IgG immune complexes were found to be significantly higher in AD patients compared to control subjects. Moreover, the levels of A?-IgG complexes were negatively correlated with the cognitive status across the groups, increasing with declining cognitive test performance of the subjects. Our results suggest a contribution of IgG-type autoantibodies to A? clearance in vivo and an increased immune response in AD, which may be associated with deficient A?-IgG removal. These findings may contribute to elucidating the role of A?-autoantibodies in AD pathophysiology and their potential application in AD diagnosis.

SUBMITTER: Maftei M

PROVIDER: S-EPMC3715516 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Increased levels of antigen-bound β-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients.

Maftei Madalina M Thurm Franka F Schnack Cathrin C Tumani Hayrettin H Otto Markus M Elbert Thomas T Kolassa Iris-Tatjana IT Przybylski Michael M Manea Marilena M von Arnim Christine A F CA

PloS one 20130718 7

Recent studies have suggested a protective role of physiological β-amyloid autoantibodies (Aβ-autoantibodies) in Alzheimer's disease (AD). However, the determination of both free and dissociated Aβ-autoantibodies in serum hitherto has yielded inconsistent results regarding their function and possible biomarker value. Here we report the application of a new sandwich enzyme-linked immunosorbent assay (ELISA) for the determination of antigen-bound Aβ-autoantibodies (intact Aβ-IgG immune complexes) ...[more]

PMID: 23874844

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Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

Project description:Background: Recent efforts have described an immunogenic component to the pathobiology of Alzheimer's disease (AD) and Parkinson's disease (PD). However, current methods of studying fluid autoantibodies, such as enzyme-linked immunosorbent assays and immunohistochemistry, are hypothesis-driven and not optimal for discovering new autoantibody biomarkers by proteome-wide screening. Recently, we developed a general mass spectrometry-based approach to identify tissue-specific autoantibodies in serum, at a proteome-wide level. In this study, we adapted the method to explore novel autoantibody biomarkers in the cerebrospinal fluid (CSF) of AD and PD patients. Methods: CSF samples were obtained from 10 headache control individuals, 10 AD patients and 10 PD patients. Antibodies present in the CSF were isolated by immobilization to protein-G magnetic beads. These antibodies were incubated with a brain tissue extract, prepared from frontal cortex, pons, cerebellum and brain stem. Protein antigens captured by the protein-G magnetic bead-bound antibodies were digested with trypsin and analyzed using mass spectrometry. Autoantibody candidates were selected by 1) detection in one or less individuals of the control group and 2) identification in at least half of the patient groups. Results: There were 16 putative autoantibody biomarkers selected from the AD group. Glia-derived nexin autoantibody was detected in eight of ten AD patients and was absent in the control group. Other AD pathology-related targets were also identified, such as actin-interaction protein, quinone oxidoreductase, sushi repeat-containing protein, metalloproteinase inhibitor 2, IP3 receptor 1 and sarcoplasmic/endoplasmic reticulum calcium ATPase 2. An additional eleven autoantibody targets were also identified in the present experiment, although their link to AD is not clear. No autoantibodies in the PD group satisfied our selection criteria. Conclusion: Our unbiased mass spectrometry method was able to detect new putative CSF autoantibody biomarkers of AD. Further investigation into the involvement of humoral autoimmunity in AD and PD pathobiology may be warranted.

Dataset Information

Increased levels of antigen-bound ?-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients.

Publications

Increased levels of antigen-bound β-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients.

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