Investigating neutrophilic inflammation as an APOE genotype-specific mediator of cognitive decline and reduced synaptic plasticity in aging - PROJECT SUMMARY
The presence of the epsilon4 allele of APOE (APOE4) is the greatest genetic risk factor for late onset
Alzheimer’s disease, 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 is unclear. The overall goals for this study are to 1) Investigate neutrophil
activation and lifespan as therapeutic targets to reduce Alzheimer’s disease 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-specific cognitive decline.
We propose that the gastrointestinal 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 cognitive decline. Our hypothesis is that APOE4 increases neutrophil
activation and lifespan in the GI, periphery, and brain, thus contributing to cognitive decline and reduced
synaptic plasticity in individuals with the APOE4 allele. 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 to
inflammatory stimuli in an isotype-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) Examine
neutrophil activation, lifespan, and function in the GI tract, periphery, and brain throughout the lifespan in
mice expressing human APOE2, APOE3, and APOE4 under the endogenous promotor (APOE-TR); 2)
Investigate roles of the microbiome and bacteria-neutrophil interactions in APOE-specific neutrophil
alterations, and 3) Determine if neutrophils mediate neuroinflammation and cognitive decline in an APOE-
specific manner in response to low level inflammatory stimuli via neutrophil depletion studies. This project
is significant because no studies have investigated APOE-specific neutrophil responses despite a proposed role
for neutrophils in Alzheimer’s disease. This project is translationally innovative and actionable because the
information gained will inform the testing of neutrophil-targeted or microbial-targeted therapeutic approaches in
Alzheimer’s disease mouse models and humans and determine if they should be tailored based on APOE
genotype.
