Trem2 R47H NSS; 5xFAD mice display age/disease progression‐dependent changes in plaques and plaque‐associated microglia, and increased plasma neurofilament light chain

• Published in: Alzheimer's & dementia Vol. 18; no. S4
• Main Authors: Tran, Kristine M, Kawauchi, Shimako, Javonillo, Dominic I, Da Cunha, Celia, Phan, Jimmy, Rezaie, Narges, Liang, Heidi Yahan, Milinkeviciute, Giedre, Gomez‐Arboledas, Angela, Forner, Stefania, Mortazavi, Ali, Tenner, Andrea J, LaFerla, Frank, MacGregor, Grant R, Green, Kim N
• Format: Journal Article
• Language: English
• Published: 01.12.2022
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.062610

Background Genome‐Wide Association Studies revealed Triggering receptor expressed on myeloid cells 2 (TREM2) R47H mutation as one of the strongest genetic risk factors for late‐onset Alzheimer’s Disease (AD). In the brain, TREM2 is a transmembrane receptor expressed exclusively by myeloid cells. Many current TREM2*R47H mouse models have observed evidence of cryptic splicing products of the mutant allele, resulting in artefactually reduced protein product. Model Organism Development & Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium at University of California ‐ Irvine has developed the Trem2 R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a level similar to the wild‐type Trem2 allele, with no evidence of cryptic splicing products from the mutant allele. Method We generated four groups – WT (C57BL6/J), Trem2 R47H homozygous (HO), 5xFAD, and 5xFAD/ Trem2 R47H HO. Coronal brain slices of 4 and 12‐month‐old mice (n=5/sex/genotype/age) were immunolabeled with Thioflavin‐S for dense‐core plaques, ionized calcium binding adaptor molecule 1 (IBA1) for microglia and lysosome‐associated membrane glycoprotein 1 (LAMP1) for neuritic dystrophy. We also measured plasma neurofilament light chain (NfL) as a surrogate measure of brain damage via Meso Scale Discovery (MSD) technology. Result Sex‐related differences in dense‐core Aß plaque burden and size are found in 4‐month 5xFAD/ Trem2 R47H, where female 5xFAD/ Trem2 R47H mice exhibit increased plaque load compared to 5xFAD mice. In males, stark reductions in plaque load are observed. This sex‐difference is not observed at 12‐month. Examination of IBA1+ microglia at 4‐month reveals significant reductions in microglia volume in both Trem2 R47H and 5xFAD/ Trem2 R47H mice compared to their controls. Notably, there is a significant impairment of plaque‐microglia interaction in 5xFAD/ Trem2 R47H at 4‐month that is rescued at 12‐month. Moreover, we find a significant increase in plaque‐associated neuritic damage in 5xFAD/ Trem2 R47H when immunolabeled with LAMP1 at 4‐month that was also absent at 12‐month. Similarly, plasma NfL levels revealed significant increases in brain damage of 5xFAD/ Trem2 R47H compared to 5xFAD at 4‐month and a trending increase at 12‐month. Conclusion Collectively, these results show the effects of the Trem2 R47H variant on plaque development and downstream pathology, highlighting sex differences as well as age/ disease progression‐dependent changes.