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

Brenda Moore,Max Robinson,Thomas Ladd,Cory C Funk,Noa Rappaport,Nilüfer Ertekin-Taner,Paramita Chakrabarty,Griffin Golde,Todd E Golde,Awilda Rosario,Mariet Allen,Priyanka Baloni,Xue Wang,Karen N McFarland,Carolina Ceballos

doi:10.26508/lsa.202101108

Abstract

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.

Highlights

Alzheimer’s disease (AD) is characterized by two hallmark pathologies, senile plaques containing amyloid-β (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of hyperphosphorylated and aggregated τ
Preformed oligomeric or fibrillar forms of Aβ42 peptide were applied to primary microglia cultures for 1- or 12-h. oAβ and fAβ were characterized by Western blot and a representative image is shown (Fig S1) demonstrating differences in the high molecular weight species between oligomeric and fibrillar Aβ preparations
Using cutoff values of a P-values corresponding to the gene significance (P-value) ≤0.05 and an absolute log2 fold change of 0.5, we identified acute transcriptional changes after fAβ application after just 1h with 997 up-regulated and 960 down-regulated genes (Fig 1A and Table S1)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by two hallmark pathologies, senile plaques containing amyloid-β (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of hyperphosphorylated and aggregated τ. Amyloid plaques are the earliest manifestations of the disease process and can appear up to 20 yr before the onset of cognitive symptoms (Bateman et al, 2012). Genetic data strongly support a causal, triggering role for aggregation and accumulation of Aβ in AD (Kunkle et al, 2019)—including the wellstudied APOE4 risk allele in late-onset AD, which reduces the clearance of Aβ from the brain (Liu et al, 2013). Despite intensive study, the precise mechanism by which accumulation of Aβ aggregates trigger the degenerative phase of the disease is not well understood

Methods

Results

Conclusion