Neurotoxicity of particulate matter and its interaction with APOE in neurodegeneration - PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia among elderly and is an apparent public health challenge in the U.S. as well as many other countries. Despite the extensive research effort on all aspects of AD, the exact causes of late-onset, sporadic AD remain elusive. Although genetic predispositions including known risk genes from human genetics studies are playing a prominent role in the pathogenesis and etiology of AD, recent growing bodies of evidence strongly suggest an emerging role of environmental contribution, particularly toxic constituents of air pollution including, but not limited to, particulate matter (PM) and metals, to the progression and onset of AD. Thus, it is critical to investigate how air pollution drives neurodegeneration and whether AD risk genes modulate its neurotoxicity and neuronal death, as an empirical example of the gene x environment (GxE) interactions to support the mechanism-based etiology of AD. As increasing number of studies in humans and animal models have confirmed the pivotal role of currently known risk genes and exposure to air pollution, independently or in combination, in AD neuropathology and neurodegeneration, we stay focuses on determining key neurotoxic mechanisms of ambient PM, the most abundant toxic constituents found in the ambient air, which subsequently leads to accelerated neurodegeneration and the clinical onset of AD. The overarching objectives of this study are 1) to comprehensively evaluate neurotoxicity of ambient PM and its environmental risk in a novel mouse model of late-onset AD, and 2) to identify key genes and mechanisms that determine the sensitivity or resilience to neuronal death triggered by PM. In this application, we include several innovative tools, such as a novel mouse model, human iPSC-derived neurons and the CRISPR-based functional genomics, to carefully assess the neurotoxicity of PM, its risk for developing and exacerbating AD phenotypes, and the GxE interactions, all of which could be more clinically relevant and applied to broader general population compared to existing findings from widely used animal models overexpressing familial AD mutations. In our knowledge, proposed in vivo and in vitro models are the best suited models to simulate and evaluate the environmental contribution to late-onset AD in humans. Thus, outcomes from this study maintain high translational significances to understand neurodegenerative mechanisms and the GxE etiology of late-onset AD. Lastly, this proposal is feasible, highly- significant, and highly-relevant to evaluate the etiology and progression of AD in the context of the GxE interactions. We believe that the outcomes could have large impact to the field, while accelerating progress towards understanding the environmental impact on the pathogenesis of AD.
