Author ORCID Identifier

https://orcid.org/0000-0002-1208-8607

Date Available

1-27-2023

Year of Publication

2022

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Physiology

Advisor

Dr. Donna M. Wilcock

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by two hallmark pathologies: amyloid-beta plaques (Ab plaques) and hyperphosphorylated, aggregated tau tangles. These pathologies are typically accompanied by the presence of neuroinflammation which is primarily mediated by microglia. Interestingly, several genetic risk factors that increase the risk of AD also have direct impacts on neuroinflammation. Of interest, Apolipoprotein E (ApoE) is the largest genetic risk factor for AD. ApoE has three isoforms- E4 confers an increased risk for AD, E3 is considered the “control” phenotype, and E2 is protective against AD. E4 plays a role in virtually all aspects of AD, including inflammation; however, the role E4 plays on specific inflammatory pathways in the human brain has been understudied. To address this gap, we used RNA from human autopsy tissue to understand the role of ApoE isoforms on specific inflammatory pathways. Interestingly, we found in pathways related to microglial activation, E4 had a dampened inflammatory response to AD pathology suggesting E4 is unable to mount an appropriate microglial response to remove AD pathology, unlike E3. Due to this finding, we then wanted to explore the effect of ApoE isoforms on microglial morphologies. Using two independent populations with microglial staining, we saw an increase in microglial activation in dementia patients in both E3 and E4 cases. Interestingly, a subtype of microglia hypothesized to support neurons, known as rod-shaped microglia, were increased in the superior medial temporal gyrus of E4-Dementia patients, suggesting an E4-driven impact on microglial morphologies. As we have shown in human tissue, ApoE isoforms play a significant role in inflammation; however, human tissue does not allow for the manipulation of specific pathways. To fine-tune our understanding of the mechanism through which ApoE isoforms affect specific inflammatory pathways, we turned to several mouse models and looked at signaling cascades and intracellular mechanisms. Based on our previous human data, we hypothesized that E4 mice would have reduced microglial activation; specifically, through E4 interference with the triggering receptor expressed on myeloid cells (TREM2) signaling cascade, due to mutations in TREM2 conferring an increased risk of AD and ApoE binding to TREM2. To understand the role of ApoE isoforms in the TREM2 cascade, two stimuli were used to target TREM2: phosphatidylserine (PS) and AL002a. PS was used to mimic neurodegeneration and AL002a was used to directly activate TREM2. By performing intracranial injections with these stimuli, we were able to see E4 microglia did not respond to the stimuli and did not mount an inflammatory response to either PS or AL002a, suggesting E4 has an inhibitory role on TREM2 signaling and could be contributing to the increased risk of AD. Collectively, this data indicates a role for E4 on neuroinflammation in AD. Further, this data suggests a potential use for precision medicine when targeting inflammation in AD based on an individual’s ApoE isoform.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.024

Funding Information

National Institutes of Health: P30-AG028383 (UK-ADRC) 2020-Present

National Institutes of Health: 1RF1AG057754-01 (DMW) 2018-2022

National Institutes of Health: 1F31AG069372-01 (CMK) 2020-2022

National Institutes of Health: 1T32 GM118292-01 (CMK) 2019-2020

National Institutes of Health: 1T32AG057461-01 (CMK) 2018-2019

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