Details

Autor(en) / Beteiligte

• Wijasa, Teodora Stella
• Sylvester, Marc
• Brocke‐Ahmadinejad, Nahal
• Schwartz, Stephanie
• Santarelli, Francesco
• Gieselmann, Volkmar
• Klockgether, Thomas
• Brosseron, Frederic
• Heneka, Michael T.

Titel

Quantitative proteomics of synaptosome S‐nitrosylation in Alzheimer’s disease

Ist Teil von

• Journal of neurochemistry, 2020-03, Vol.152 (6), p.710-726

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2020

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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. Loss of synapses and neuroinflammation constitute early events in pathogenesis of Alzheimer´s disease (AD). Both events might be linked if inflammation‐ induced mediators affect the synapses or synaptic proteins, potentially providing new biomarker candidates. This proteomics study quantified S‐nitrosylated synaptosomal proteins as a fingerprint of neuroinflammation‐induced nitric oxide release. Synaptosomes were isolated from human AD patient brain tissue, as well as APP/PS1 mice at 3 and 12 months of age, followed by mass spectrometry. Differentially nitrosylated proteins were evaluated and the 10 most promising targets for biomarker validation were discussed.