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.