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.