A Novel Approach to Study the Role of S-nitrosylation in Alzheimer’s Disease

Assistant Professor Moran Benhar

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by progressive loss of memory and other cognitive functions.  The two core pathological hallmarks of AD are amyloid plaques and neurofibrillary tangles, which are thought to contribute to the death of neurons leading and disease progression. These events are commonly associated with inflammation of the nervous tissue and elevated levels of free radicals, in particular nitric oxide. This proposal is focused on mechanisms that link increased nitric oxide levels to neuronal damage in AD.

Many of the cellular effects of nitric oxide are mediated by a process known as S-nitrosylation, in which nitric oxide modifies cysteine residues in various proteins. S-nitrosylation is known to regulate the activity of multiple proteins that are implicated in AD pathogenesis, but, whether and how this process may affect AD progression is not well understood.

Here, we propose to investigate the involvement of S-nitrosylation in AD. First, we will apply a novel method to identify nitrosylated proteins in the mouse brain using an established animal model of AD. We will then examine if S-nitrosylation regulates the activity of selected proteins indentified in the proteomic screen. We will also explore if interventions that reduce S-nitrosylation may result in improved neuronal survival.

This study will provide a better understanding of the mechanisms and roles of nitric oxide in Alzheimer’s disease and may suggest novel targets for future therapeutic intervention.Moran Benhar