Assessing impaired neuroinflammation associated with Apolipoprotein E4

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PROJECT SUMMARY/ABSTRACT: Alzheimer’s Disease (AD) remains the leading cause of dementia worldwide and 6th leading cause of death in the United States. While the majority of AD cases have no clear genetic cause, a few genetic risk factors for developing AD have been identified. One of the most significant genetic risk factors is Apolipoprotein E (ApoE). Of the three identified ApoE isoforms, ApoE4 confers an increased risk of AD, ApoE3 is believed to be the “control” phenotype, and ApoE2 has been shown to be protective for AD. Interestingly, ApoE has been shown to interact with a surface receptor on microglia, triggering receptor expressed on myeloid cells 2 (TREM2) which has also been shown to confer an increased risk of AD. Recent studies suggest this interaction drives microglial gene expression and function toward an activated microglial state in the presence of neurodegeneration, suggesting a role for ApoE in the inflammatory response seen in AD. While the AD field has established ApoE and TREM2 as risk factors for AD, the mechanistic insights into these risk factors remain murky at best. Preliminary results for this project, using autopsy tissue from the University of Kentucky– Alzheimer’s Disease Center Brain Bank, suggests ApoE3 patients with AD have a neuroinflammatory response differing from that seen in ApoE3 patients without AD, suggesting that the ApoE3 isoform is responding to AD pathology. In contrast, ApoE4 patients with AD tend to be in a state of neuroinflammation similar to that found in ApoE3 patients without AD, suggesting they cannot respond to the AD pathology. This project aims to determine the impact of ApoE isoforms on the inflammatory cascade in both mouse and human models. We hypothesize that the ApoE4 isoform impairs a beneficial neuroinflammatory response in AD and has a weakened interaction with TREM2. To delve into the differences highlighted by the preliminary data, two approaches will be used to determine the impact of the ApoE isoform dependent mechanism. First, we will continue investigating the neuroinflammatory profile of AD autopsy brains by determining microglial morphology in ApoE3/3 and ApoE4/4 patients with AD to compare activation states of the microglia. We will also perform NanoString Digital Spatial Profiling to look at proteins surrounding AD hallmarks and microglia. These approaches will allow for a deeper understanding of how these changes seen from the preliminary data associate with the pathology. Our second approach will use animal models to target TREM2 and investigate the impact ApoE isoforms have on TREM2 activation. We will target TREM2 activation using phosphatidylserine and a TREM2 agonizing antibody to allow for a more comprehensive view of the impact ApoE isoforms have on TREM2 activation. This project overall aims to investigate the importance of ApoE isoforms on neuroinflammation to in an ApoE isoform specific manner. Cumulatively, this proposal provides adequate time and with excellent facilities to acquire training in necessary laboratory techniques, data analysis, scientific communication, manuscript writing, and mentoring to provide a strong foundation to achieve my goal of an independent investigator in neuroinflammation.