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THE R47H TREM2 VARIANT MODIFIES ALZHEIMER'S DISEASE PATHOLOGY AND NEUROINFLAMMATION IN A NOVEL KNOCK-IN MOUSE MODEL
Abstract   Open access   Peer reviewed

THE R47H TREM2 VARIANT MODIFIES ALZHEIMER'S DISEASE PATHOLOGY AND NEUROINFLAMMATION IN A NOVEL KNOCK-IN MOUSE MODEL

Paul Cheng-Hathaway, Taylor Jay, Erin Reed, Shane Bemiller, Shweta Puntambekar, Guixiang Xu, Colleen Carlo, Richard Ransohoff, Gary Landreth and Bruce T. Lamb
Alzheimer's & dementia, Vol.12(7S Part 5), pp.P243-P243
07/2016
DOI: 10.1016/j.jalz.2016.06.435
url
https://doi.org/10.1016/j.jalz.2016.06.435View
Published (Version of record) Open Access

Abstract

Background Genetic variants in TREM2 have been associated with several neurodegenerative diseases. Recessive loss of function mutations in TREM2 results in Nasu-Hakola disease, characterized by bone cysts and a non-AD dementia while the heterozygous R47H variant in TREM2 confers increased risk for late onset AD. Several groups have postulated that the R47H variant is loss of function. However, in our previous study, we found that complete TREM2 deficiency in an AD mouse model resulted in a significant attenuation of AD-like pathology. It therefore becomes critical to determine whether the R47H variant in AD exhibits loss of function, gain of function, dominant negative function or a combination of functions on AD phenotypes. Methods To examine the role of the R47H TREM2 variant in AD pathogenesis, genome edititing technology was utilized to introduce the R47H variant into the mouse Trem2 gene (Trem2R47H/+) and the resulting mice subsequently mated to the APPPS1 mouse model of AD. APPPS1;Trem2R47H/+, APPPS1;Trem2+/+, APPPS1;Trem2-/+, and APPPS1;Trem2-/- mice were aged to 4 months of age and examined for amyloid production and deposition, neuroinflammation and macrophage accuulation and proliferation. Results Using CRISPR/Cas genome editing, we generated novel transgenic animals containing the AD risk allele, R47H. For the current studies, we compared APPPS1;Trem2R47H/+, APPPS1;Trem2+/+, APPPS1;Trem2-/+, and APPPS1;Trem2-/- mice at 4 months of age via biochemical and histological studies. Strikingly, these studies demonstrated that APPPS1;Trem2R47H/+ mice exhibited both loss and gain of function(s) with regards to AD phenotypes, including amyloid deposition, neuroinflammation and macrophage accumulation when compared to the three other genotypes (APPPS1;Trem2+/+, APPPS1;Trem2-/+, and APPPS1;Trem2-/-). Conclusions The current studies report on the generation of a unique mouse model of the R47H TREM2 risk allele via genome editing that was subsequently crossed to the APPPS1 mouse model of AD. These findings suggest that the R47H AD risk variant exhibits a variety of both loss and gain of function(s) depending upon the AD phenoytpe that is examined and also suggests that TREM2's function(s) are likely pleiotropic in nature. Further experiments are needed to understand the mechanism via which the R47H TREM2 variant impacts myeloid cell function as well as other AD phenotypes (including neruonal function and tau pathology) that will ultimately assist in designing TREM2- focused therapies for AD.

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