[en] Increasing evidence suggests that both synaptic loss and neuroinflammation constitute early pathologic hallmarks of Alzheimer's disease. A downstream event during inflammatory activation of microglia and astrocytes is the induction of nitric oxide synthase type 2, resulting in an increased release of nitric oxide and the post-translational S-nitrosylation of protein cysteine residues. Both early events, inflammation and synaptic dysfunction, could be connected if this excess nitrosylation occurs on synaptic proteins. In the long term, such changes could provide new insight into patho-mechanisms as well as biomarker candidates from the early stages of disease progression. This study investigated S-nitrosylation in synaptosomal proteins isolated from APP/PS1 model mice in comparison to wild type and NOS2-/- mice, as well as human control, mild cognitive impairment and Alzheimer's disease brain tissues. Proteomics data were obtained using an established protocol utilizing an isobaric mass tag method, followed by nanocapillary high performance liquid chromatography tandem mass spectrometry. Statistical analysis identified the S-nitrosylation sites most likely derived from an increase in nitric oxide (NO) in dependence of presence of AD pathology, age and the key enzyme NOS2. The resulting list of candidate proteins is discussed considering function, previous findings in the context of neurodegeneration, and the potential for further validation studies.
Disciplines :
Neurology
Author, co-author :
Wijasa, Teodora Stella; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Sylvester, Marc ; Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany
Brocke-Ahmadinejad, Nahal; Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Gieselmann, Volkmar; Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany
Klockgether, Thomas; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurology, University of Bonn, Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Quantitative proteomics of synaptosome S-nitrosylation in Alzheimer's disease.
This work was supported in the frame of the BIOMARKAPD (01ED1203B) project within the EU Joint Programs for Neurodegenerative Diseases Research (JPND), the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2011-278850 (INMiND) and the EU-IMI program n° 115568 (AETIONOMY). Michael T. Heneka is a member of the Cluster of Excellence “Immunosensation”. The Banner Sun Health Research Institute Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke, U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders; National Institute on Aging, P30 AG19610 Arizona Alzheimer’s Disease Core Center; Arizona Department of Health Services, Arizona Alzheimer’s Consortium; Arizona Biomedical Research Commission, Arizona Parkinson's Disease Consortium; Michael J. Fox Foundation for Parkinson’s Research. Thanks to Dr. Elizabeth Campbell and Dr. Roisin McManus for proofreading the article. MTH holds editorship at the Journal of Neurochemistry. All experiments were conducted in compliance with the ARRIVE guidelines.This work was supported in the frame of the BIOMARKAPD (01ED1203B) project within the EU Joint Programs for Neurodegenerative Diseases Research (JPND), the European Union's Seventh Framework Programme (FP7/2007‐2013) under grant agreement n° HEALTH‐F2‐2011‐278850 (INMiND) and the EU‐IMI program n° 115568 (AETIONOMY). Michael T. Heneka is a member of the Cluster of Excellence “Immunosensation”. The Banner Sun Health Research Institute Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke, U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders; National Institute on Aging, P30 AG19610 Arizona Alzheimer’s Disease Core Center; Arizona Department of Health Services, Arizona Alzheimer’s Consortium; Arizona Biomedical Research Commission, Arizona Parkinson's Disease Consortium; Michael J. Fox Foundation for Parkinson’s Research. Thanks to Dr. Elizabeth Campbell and Dr. Roisin McManus for proofreading the article. MTH holds editorship at the Journal of Neurochemistry.
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