Microglia show differential transcriptomic response to Aβ peptide aggregates ex vivo and in vivo

• DOI: 10.26508/lsa.202101108
• Publication Date: 2021-06-14T17:10:13Z
• Authors: Karen N McFarland; Carolina Ceballos; Awilda Rosario; Thomas Ladd; Brenda Moore; Griffin Golde; Xue Wang; Mariet Allen; Nilüfer Ertekin-T...; Cory C Funk; Max Robinson; Priyanka Baloni; Noa Rappaport; Paramita Chakrabarty; Todd E Golde
• Keywords: Male; 0301 basic medicine; Mice, Inbred C3H; Amyloid beta-Peptides; Primary Cell Culture; Brain; Gene Expression; Mice, Transgenic; Neurofibrillary Tangles; Mice, Inbred C57BL; Amyloid beta-Protein Precursor; Disease Models, Animal; Mice; 03 medical and health sciences; Alzheimer Disease; Animals; Female; Microglia; Transcriptome; Research Articles

Aggregation and accumulation of amyloid-β (Aβ) is a defining feature of Alzheimer’s disease pathology. To study microglial responses to Aβ, we applied exogenous Aβ peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system-level transcriptional changes and then compared these with transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change in response to Aβ. Transcriptomic responses to oligomeric or fibrillar Aβ in primary microglia, although partially overlapping, are distinct and are not recapitulated in vivo where Aβ progressively accumulates. Furthermore, although classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar Aβ can be distinguished.