Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies

Abstract

Alzheimer’s disease (AD) is arguably the most common cause of dementia in the elderly and is marked by progressive synaptic degeneration, which in turn leads to cognitive decline. Studies in patients and in various AD models have shown that one of the early signatures of AD is neuronal hyperactivity. This excessive electrical activity contributes to dysregulated neural network function and synaptic damage. Mechanistically, evidence suggests that hyperexcitability accelerates production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that contribute to neural network impairment and synapse loss. This review focuses on the pathways and molecular changes that cause hyperexcitability and how RNS-dependent posttranslational modifications, represented predominantly by protein S-nitrosylation, mediate, at least in part, the deleterious effects of hyperexcitability on single neurons and the neural network, resulting in synaptic loss in AD.

Anxiolytic-like Activity, Antioxidant Properties, and Facilitatory Effects on the Short-Term Memory Retention of Molsidomine in Rats

“…NO has been shown to play an important role in the signaling and regulation of glutamatergic synapses by modulating ion channel firing, membrane fusion, fission, and compartmentalization or by facilitating protease-mediated protein degradation [ 17 ]. In particular, S-nitrosylation has been suggested to be involved in the pathogenesis of various neurodegenerative disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s disease [ 11 , 18 , 19 ]. Neuronal inflammation, which characterizes these pathological states, is largely associated with pathogenic pathways involved in NO production [ 20 ].…”

Primary and Secondary Coordination Sphere Effects on the Structure and Function of S-Nitrosylating Azurin

“…S -Nitrosylation is a reversible post-translational protein modification that serves as a significant route for cellular NO signaling, controlling functions such as apoptosis, muscle contraction, and vasodilation . As a result, dysregulation of S -nitrosylation has been correlated with a plethora of diseases, including cancer initiation, − Alzheimer’s disease, − Parkinson’s syndrome, − and cardiovascular disease. − There is significant evidence that this process relies on metalloproteins to catalyze the S -nitrosylation of protein cysteine thiols, followed by transfer of NO by trans- S -nitrosylation to other acceptor proteins or low molecular weight thiols such as glutathione or coenzyme A. , While S -nitrosylation has been shown to be catalyzed by Cu II - and Fe II -containing enzymes, such as ceruloplasmin and hemoglobin, ,− thousands of potential S -nitrosylated proteins have been identified using proteomics methods, ,− highlighting the potential role of less well-characterized metalloenzymes in the regulation or dysregulation of NO.…”