Wolfe, Cody
(2020)
Trem2 Deficiency Differentially Affects the Phenotype and Transcriptome of Human APOE3 and APOE4 mice: The Role of APOE and TREM2 in Alzheimer’s Disease.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide and a significant public health concern impacting not only patients, but their families and caregivers as well. Extracellular deposits of amyloid beta Aβ in the brain called amyloid plaques and intracellular tau aggregates called neurofibrillary tangles are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, genetic risk factors, and environmental influences. The inheritance of Apolipoprotein E ε4 (APOEε4) and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Emerging evidence from protein binding assays suggest that APOE and APOE-containing lipoproteins bind to TREM2 in the brain as well as periphery. This raises the possibility of an APOE-TREM2 interaction modulating aspects of AD pathology, potentially in an isoform-specific manner. This dissertation aimed to investigate this interaction using complex AD model mice - a crossbreed of Trem2ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoform, evaluating cognition, steady-state and dynamic amyloid pathology, glial response, and whole-brain transcriptomics. We found that Trem2 deletion had the following effects on the phenotype: a) reduced plaque compaction but no effect on steady-state plaque load; b) decreased microglia recruitment to plaques; c) increased plaque growth in correlation with reduced microglia barrier, an effect that is dependent on the stage of amyloid deposition; d) isoform dependent effect on plaque-associated APOE; e) worsened memory in APP but not in WT littermates. Gene expression analysis identified the Trem2 signature as a cluster of highly interconnected immune response genes commonly downregulated as a result of Trem2 deletion in all experimental groups, including Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1 and Spi1/PU.1. Several of the Trem2 signature genes had higher expression in APP/E4 versus APP/E3 mice, a result validated for Clec7a and Csf1r by FISH, and for APOE by immunohistochemistry. In contrast, Tyrobp and several genes involved in the C1q complement cascade had higher expression levels in APP/E3 versus their APP/E4 counterparts. Collectively, this dissertation provides evidence as to the phenotypic and transcriptomic effects regarding the interplay between human APOE isoform and Trem2 deletion in association with AD pathology.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
10 September 2020 |
| Date Type: |
Publication |
| Defense Date: |
7 August 2020 |
| Approval Date: |
10 September 2020 |
| Submission Date: |
8 June 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
125 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Environmental and Occupational Health |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Trem2, APOE, Transcriptomics, Microglia, Neuroinflammation, Alzheimer’s disease, Amyloid plaques, Neurodegeneration, APP transgenic mice, RNA-sequencing |
| Date Deposited: |
11 Sep 2020 02:34 |
| Last Modified: |
11 Sep 2020 02:34 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39604 |
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