Role of TREM2 deficiency in Alzheimer’s disease model mice expressing human APOE3 or APOE4 Molecular and cell biology/neuroinflammation

• Published in: Alzheimer's & dementia Vol. 16; no. S2
• Main Authors: Fitz, Nicholas F., Nam, Kyong Nyon, Letronne, Florent, Wolfe, Cody M., Playso, Brittany E., Lefterov, Iliya, Koldamova, Radosveta
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.046343

Abstract Background Alzheimer’s Disease (AD) is a multifactorial neurodegenerative disease influenced by aging, genetic, and environmental risk factors. Inheritance of APOE ε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 ( TREM2 ) are two major genetic risk factors for AD, surprisingly little is known about the interplay between these two risks. TREM2 is a receptor of the innate immune system expressed on microglia, indicating a role in AD related neuroinflammation. Recent data showed APOE can bind to TREM2, in an isoform specific manner, thus raising the possibility of an APOE‐TREM2 interaction affecting TREM2 signaling and microglial function. We hypothesize that TREM2 deficiency will modulate the pathological phenotype and microglial transcriptome in AD model mice expressing human APOE3 and APOE4 in a disease progressions‐dependent manner. Method In this study, we crossed Trem2 expressing and Trem2 ko mice with APP/PSEN1dE9 mice expressing human APOE3 or APOE4 genes to investigate whether the loss of Trem2 impacts: amyloid pathology, glial response, and whole‐brain transcriptome. To determine the disease progression‐dependent impact of Trem2 deficiency we assessed the AD model mice at an early stage (3.5 mo) and more advanced stage (6.5 mo). Result Our study provides evidence that Trem2 deletion worsened cognitive performance, diminished microglia barrier around amyloid plaques, but did not impact overall amyloid load in either APOE genotype at both age groups assessed. Using multi‐color time stamp in vivo plaque labeling for assessing growth kinetics of amyloid plaques, we determined that Trem2 deletion increased plaque diffusivity and growth of newly formed plaque in both APOE isoforms. To get further insight in the specific effects of Trem2 deficiency in relationship to APOE isoform, we performed RNA‐seq using whole brain tissue followed by comparison to known cell‐type specific genetic signatures including known disease associated microglial (DAM) genes. Transcriptionally, we identified: 1) a sub‐set of immune response genes including DAM and homeostatic microglial genes that are downregulated in all experimental groups and comprise the Trem2 signature, and 2) differentially expressed genes that are characteristic for each APOE genotype and age group. Conclusion This study significantly increases our understanding of the interaction between APOE isoforms and TREM2 in association with AD pathology.