Cody Wolfe of the Environmental and Occupational Health defends his dissertation, entitled "Trem2 deficiency differentially affects the phenotype and transcriptome of human APOE3 and APOE4 mice: The Role of APOE and TREM2 in Alzheimer’s Disease."

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 suggests that APOE binds to TREM2, and APOE-containing lipoproteins 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 investigated this interaction using complex AD model mice - a crossbreed of Trem2^ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoform. We evaluated 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 a 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.

Dissertation Advisor:
Radosveta Koldamova, Department of Environmental & Occupational Health, Graduate School of Public Health, University of Pittsburgh

Committee members:
Iliya Lefterov, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh

Aaron Barchowsky, Department of Environmental & Occupational Health, Graduate School of Public Health, University of Pittsburgh

Nicholas Fitz, Department of Environmental & Occupational Health, Graduate School of Public Health, University of Pittsburgh

Bistra Iordanova, Department of Bioengineering, University of Pittsburgh