Investigating neutrophilic inflammation as an APOE genotype-specific mediator of neuroinflammation and cognitive decline in aging - Project Summary The presence of the 4 allele of APOE (APOE4) is the greatest genetic risk factor for late onset Alzheimer’s disease (AD), increasing the risk approximately 12-fold when homozygous for APOE4 compared to the most common APOE3/APOE3 genotype. However, the mechanisms by which different APOE alleles mediate Alzheimer’s risk are unclear. The overall goals for this study are to 1) Investigate neutrophil activation and lifespan as therapeutic targets to reduce AD risk or progression in the context of different APOE genotypes and 2) Identify microbial interactions that represent promising targets to reduce neutrophilic inflammation in the context of different APOE genotypes. A multitude of data demonstrate that individuals with different APOE genotypes vary in their responses to inflammatory stimuli, and ApoE- modulated neuroinflammation is emerging as a potential new mediator of APOE genotype-specific cognitive decline. We propose that the gastrointestinal (GI) and peripheral immune systems represent a likely bridge between infection or microbial dysbiosis and neuroinflammation, and that neutrophils, as the most abundant leukocyte with great potential for inflammatory damage, mediate altered responses in individuals with different APOE alleles to drive neuroinflammation and cognitive decline. Our hypothesis is that APOE4 increases neutrophil activation and lifespan in the GI, periphery, and brain, thus contributing to neuroinflammation and cognitive decline. This hypothesis is based on compelling evidence from published work and our preliminary data. Studies have demonstrated that neutrophils infiltrate the brain vasculature and parenchyma during AD and neutrophil activation in the periphery corresponds with disease progression in AD. Our preliminary data suggests that APOE alters neutrophil activation in a genotype- specific manner, as has been observed previously in glial cells. We will address our hypothesis and achieve our study goals by pursuing the following three aims: 1) Investigate neutrophil lifespan, activation, and functionality in the GI tract, periphery, and brain based on APOE genotype and age in mice expressing human APOE2, APOE3, and APOE4 under the endogenous promotor (APOE-TR); 2) Investigate microbiome changes longitudinally in APOE-TR mice and ApoE modulation of neutrophil responses to APOE genotype-specific commensal bacteria and A; and 3) Investigate neutrophils as mechanistic drivers of neuroinflammation and cognitive impairment in response to inflammatory stimuli in the context of different APOE genotypes. This project is significant because no studies have investigated APOE-specific neutrophil responses despite a proposed role for neutrophils in AD. This project is translationally innovative and actionable because the information gained will inform the testing of neutrophil-targeted or microbial-targeted therapeutic approaches in AD mouse models and humans and determine if they should be tailored based on APOE genotype.
