Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein Snitrosylation of C3

Hongmei Yang, Chang Ki Oh, Haitham Amal, John S. Wishnok, Sarah Lewis, Emily Schahrer, Dorit Trudler, Tomohiro Nakamura, Steven R. Tannenbaum*, Stuart A. Lipton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 (SNOTRAP) 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.

Original languageAmerican English
Article numberade0764
JournalScience advances
Volume8
Issue number50
DOIs
StatePublished - 14 Dec 2022

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