Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

PROJECT SUMMARY/ABSTRACT (AD-focused Administrative Supplement)
The estimated number of people with dementia is predicted to triple by 2050 worldwide. Together with the lack
of effective treatments to stop, slow or prevent Alzheimer’s disease (AD) and its related dementias, the best
strategy to limit the predicted incidence is to mitigate AD risk factors. Exposure to ambient particulate matter
(PM) is emerging as a modifiable environmental risk factor for AD. However, the mechanism by which PM
exposure contributes to the development of AD is not known. Our previous research has shown that exposures
to ultrafine particles (UFP) and diesel exhaust (DE) in mice lead to chronic inflammation, increased lipid
peroxidation in lung and systemic tissues, disturbances in lipid metabolism and plasma lipoproteins, and the
development of liver steatosis and atherosclerosis, all components of the commonly called cardiometabolic
syndrome. Recent studies suggest that cardiovascular and metabolic disorders may play a critical role in the
development of AD. In fact, AD and cardiometabolic syndrome share major risk factors, in addition to
cerebrovascular and cardiovascular changes occurring years before symptoms occur. We will augment the
Parental R01 (ES033703, RESTORE RFA) by extending its focus on hepatic steatosis and atherosclerosis with
the analyses of brain tissue in the same hyperlipidemic mouse model (low-density lipoprotein knockout, Ldlr KO),
placed on a high fat diet (HFD). Importantly, Ldlr deficiency and HFD administration have been associated with
worsened AD-related phenotypes and cognitive dysfunction in a transgenic mouse model of AD through
impairment of antioxidant system defenses leading to oxidative stress and neuronal apoptosis. Therefore, while
this is not a typical mouse model for the study of AD, we do expect significant neuroinflammatory and
neurodegenerative effects. Our overall objective is to identify critical pathways in the Lung-Heart-Brain Axis
that could be involved in the development of chronic inflammation in the brain. Our hypothesis for this AD-
focused Research Supplement is that particulate matter inhalation exposure promotes proinflammatory and
degenerative effects in the brain of Ldlr null mice fed a HFD, and retards the resolution of those effects after
halting the feeding of the HFD. Our hypothesis will be tested via the following aims: Supplemental Specific Aim
1) Determine neuroinflammatory effects, AD-relevant changes in the brain and neurobehavioral alterations
induced by diesel exhaust exposure and feeding of a HFD, and how such exposure affects resolution of those
effects after cessation of the HFD; and Supplemental Specific Aim 2) Assess neuroinflammatory effects, AD-
relevant changes in the brain and neurobehavioral alterations induced by UFP exposure and feeding of a HFD,
and how such exposure affects resolution of those effects after cessation of the high fat diet. Results from this
Supplement could provide convincing preliminary data for additional proposals to investigate environmental
factors that may induce AD and other potential drivers of cognitive decline.

Grant Number: 3R01ES033703-05S1
NIH Institute/Center: NIH
Principal Investigator: Jesus Araujo