Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein S-nitrosylation of C3.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36516243.
- Also identified by DOI 10.1126/sciadv.ade0764 and PMC identifier 9750152.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (<i>SNO</i>TRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.
Medical subject headings
- Alzheimer Disease