UC Irvine

Alzheimer’s disease (AD) is the leading cause of dementia among the elderly and sixth leading cause of death in the US. No effective therapeutic intervention is currently available to treat, cure or halt this devastating disease. The prevalence of AD is expected to rise rapidly in coming years and is predicted to overwhelm our socioeconomic reserves. Thus, unveiling critical pathogenic mechanisms of the disease and risk factors that modulate the disease progression and onset is an urgent matter to slow this upswell. While aging and genetics are unequivocal risk factors for AD, there is a growing evidence supporting the pivotal role of environmental or modifiable factors in contributing the onset of AD. Among them, air pollution has recently been highlighted as a prominent culprit accelerating cognitive decline and increasing a risk for AD. However, little work has been done to elucidate its underlying molecular mechanisms by which exposure to air pollution contributes to the pathological development of AD. The purpose of this dissertation is to investigate the neurotoxic effects of airborne particulates in a humanized amyloid mouse model of AD. Previous reports indicate that PM exposure in non-AD model mice increases inflammatory markers such as cytokines, glial activation, and oxidative stress in the CNS and may increase expression of native mouse amyloid or alter its processing. Thus, we hypothesize that exposure to ultra-fine particulates exacerbates memory impairment by increasing neuroinflammation and amyloid β burden in a humanized amyloid mouse model of AD. To test this, we exposure wild-type and AppNL-G-F/+-KI mice to concentrated ultra-fine particulate matter both in utero and at adult ages. We show exposure dependent decreases in memory behavior tasks, as well as increases in Aβ plaque burden in the AppNL-G-F/+-KI model. However, memory impairment occurs independently of plaque burden increase, and only in the in utero exposure group were neuroinflammatory markers increased. In the adult exposure, we instead saw a decrease in the astrocytic glutamate transporter GLT-1. Previous work has shown a link between glutamate transporter loss and tau pathology, indicating a potential amyloid independent pathway linking particulate exposure and AD pathology. This research provides evidence of Aβ plaque burden increase dependent only on particulate exposure, as well as evidence that exposure during development impacts AD neuropathology in adult mice.