This application, submitted in response to solicitation NOT-AG-18-008 AD (?Alzheimer's Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease?), is for a supplement to a Phase II SBIR grant (parent project) recently awarded to Vala Sciences Inc (R44ES026268 ?Assay of chemicals for Parkinson's toxicity in human iPSC-derived neurons?). The goal of the parent project is to develop assays to test environmental toxicants for toxic effects relevant to Parkinson?s Disease (PD). The supplemental project will develop assays to test environmental agents for toxicity relevant to Alzheimer?s Disease (AD). We will focus on 2.5 micron particles from air pollution (PM2.5) which has been strongly implicated in increasing AD, PD, and Autism Spectrum Disorders (ASD), and the assay system we will develop will feature cortical neurons (glutamatergic = excitatory, and GABAergic = inhibitory) and microglia (MG) derived from human induced pluripotent stem cells (iPSC-glutamatergic neurons and iPSC-MG). MG will be included because neuroinflammation is a key component of AD, PD, and other neurodegenerative/neurodevelopmental diseases. Also, as the epsilon-4 variant of Apolipoprotein E (APOE4, ApoE4) is responsible for the greatest genetic risk of late-onset AD, and likely increases the susceptibility to environmental toxicants, variations of the assay will be developed with neurons and MG representing APOE3/3, APOE3/4, and APOE4/4 genotypes. The supplemental project will greatly increase our understanding of how air pollution increases the prevalence of AD (and also PD) and methods and reagents developed by the supplemental project (improved methods for producing iPSC-MG, and an isogenic iPSC panel representing different APOE genotypes) will have benefits beyond this project, as the basic assay system will potentially be useful in identifying therapeutics against AD, PD, ASD and neuroafflictions such as traumatic brain injury and stroke.
Alzheimer?s Disease (AD), the most common neurodegenerative disease (neurons within the brain of AD patients die off and are not replaced, leading to loss of memory), afflicts 5.5 million people in the US and increases with age (32% of those >85 yr). Alarmingly, air pollution increases the incidence of AD, and 2.5 micron particulate matter (PM2.5) from diesel exhaust is implicated. Also, people whose genes include a variant of apoplipoprotein E (ApoE4) are more likely to develop AD. We will develop an assay to test PM2.5 (collected by our colleagues from air in Beijing, China) on neurons and ?microglia?, which are ?immune cells of the brain? (similar to white blood cells). The neurons and microglia will be derived from stem cells (a type of stem cells derived from skin cells [obtained from painless skin biopsies], not embryos). PM2.5 will be added and effects on cell function will be quantified via robotic microscopes, digital cameras, and sophisticated image-analysis algorithms. Neurons and microglia featuring ApoE4 will also be tested. The results will help us understand how air pollution increases AD and the effect of ApoE4. Furthermore, in future studies, variants of the assay will be used to identify potential therapeutics for AD, Parkinson?s Disease, Autism, traumatic brain injury and stroke.
