Aberrant protein S-nitrosylation mediates Gene-Environment Interactions in AD/ADRD - Project Summary Alzheimer’s disease (AD) and AD-related dementias (ADRD) represent the most common forms of neurodegenerative disease in patients above 65 years of age. Growing evidence has suggested that the potential causes of AD/ADRD in the aging population are multi-faceted and are likely mediated through an interaction of lifestyle, genetic, and environmental risk factors. As an example of environmental factors, air pollution caused by car exhaust and power plant emissions, contains hazardous airborne substances, such as fine particulate matter (PM) with nitric oxide-related species (NOx), and is associated with increased risk of cognitive impairment in AD. However, the molecular mechanisms underlying the interplay of genetic risk factors (such as ApoE4) and environmental air pollution exposures (termed GxE) in AD/ADRD pathogenesis remain largely unknown. In this application, we propose to study the targets of aberrant protein S-nitrosylation after exposure to PM/NOx as found in air pollution in order to better characterize this exposome and to find new potential targets of therapy for AD. In fact, we were the first group to show that increased levels of NO/NOx contribute to synaptic damage, a major correlate to cognitive decline in sporadic AD/ADRD, via aberrant protein S-nitrosylation forming SNO-proteins. For example, our recent findings in human postmortem brains from AD patients vs. age-matched controls of both sexes and diverse backgrounds has produced evidence for aberrantly S-nitrosylated proteins (SNO-proteins) in AD human brain that cause metabolic energetic compromise and resulting synaptic loss in AD, the major neuropathological correlate to cognitive decline. For our proposed work, we will use human induced pluripotent stem cell (hiPSC)-derived 2D cultures and 3D cerebral organoids as well as in vivo xenotransplantation models. In Specific Aims 1 and 2, we will determine the effect of the exposome, represented by PM/NOx present in air pollution, by assessing the S- nitrosoproteome in hiPSC-derived 2D cultures and 3D cerebral organoids as well as in mouse AD models carrying AD-related genetic variants vs. isogenic WT controls after exposure to PM/NOx. In Aim 3, we will identify and validate aberrantly S-nitrosylated proteins formed in response to the PM/NOx exposome as potential therapeutic targets in AD brain using hiPSC-derived 2D cultures and 3D cerebral organoids as well as in vivo mouse xenotransplantation models. We can determine causality of the aberrantly S-nitrosylated proteins by testing non-nitrosylatable mutant forms of the proteins, as we have previously described. Thus, the significance of these S-nitrosoproteomic changes is that they will be linked to cognitive decline in AD, and therefore S-nitrosylated protein changes arising from the exposome may represent potential new therapeutic targets.
