Western diet (WD) has become a staple of our modern world. The change in diet, along with overnutrition and sedentary behavior has led to record numbers of individuals with obesity, and a global epidemic of metabolic diseases including cardiovascular disease (CVD). CVD is a chronic inflammatory disease driven by persistent sterile inflammation, and contributes to a plethora of other inflammatory conditions, such as diabetes and neurodegeneration. We have previously shown that the innate immune system plays an important role in the development of atherosclerosis, the main cause of CVD, however, the exact factors leading to the systemic, low-grade inflammation (termed metaflammation) were unknown.
In the first funding period, we carried out an unbiased large-scale multi-omic in vivo screen, evaluating 1100 parameters. We found that the consumption of WD in models of atherosclerosis increased the serum levels of specific lipids. In vitro, we identified that these lipids could trigger an inflammatory response in macrophages, together linking diet with innate immune driven inflammation.
Obesity, atherosclerosis, and metaflammation are risk factors for the development of dementia, however, the underlying molecular mechanisms are unknown. Thus, in the second funding period, we aim to determine whether WD-induced lipids are the molecular component linking metaflammation during obesity and arteriosclerosis with neurodegeneration.
First, we will compare mouse models for Alzheimer’s disease pathology with atherosclerosis after WD, where subgroups of mice will have the identified lipids depleted via a gene targeting strategy. We will cross-examine the effect of WD-induced lipids on central and peripheral inflammation across both models to better understand how atherosclerosis plus WD can affect neuroinflammation and vice versa. Second, we will perform spatial transcriptomics on the brains from these mice to reveal the spatial organization of blood brain barrier (BBB) dysfunction, myeloid and neuronal cell changes. Finally, results will be confirmed in human cohorts and in human PBMCs.