A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology

Abstract

Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimer's disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-β. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-b plaques, in contrast with the response to oligomeric Aβ. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome.

Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

“…This is consistent with previous observations in mouse models of C9orf72 deficiency, supporting the idea of ablation of these specific phenotypes as a result of the C9orf72 haploinsufficiency (Supplementary Figure 3) (7,(25)(26)(27). These data also indicate that there might be strong similarities between the contribution of microglia across different neurodegenerative disorders (21,24,(28)(29)(30). To confirm our findings, we repeated our gene enrichment analysis using several specific transcriptional pathways that account for different aspects of microglial function.…”

“…Similarly, we also find that diminished levels of C9orf72 result in an impaired transition into DAM and HLA responses, and reduced engagement in phagocytic and lysosomal transcriptional programs. This is not a unique phenotype of microglia harboring C9orf72 mutations, and have been observed before in pathogenic genetic variants in TREM2 and APOE (24). These findings indicate that the inflammatory substrate and microglial contribution is different in C9orf72 and sALS pathology, and additional insights will be crucial to define tailored therapeutic strategies for groups of patients with different pathogenic contributors.…”

“…We have recently mapped the transcriptomic changes occurring in human microglia during amyloid- pathology using a xenotransplantation mouse model (24). To shed light on whether C9orf72 HRE modifies the microglial phenotype, we performed a gene enrichment analysis and mapped those transcriptomic signatures in our dataset).…”

Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

“…), see Figure 4B. This population is enriched in human leukocyte antigen (HLA) genes 37,38 consistent with a concurrent unfolded protein response (mediated by HSP90 and HSPA chaperones) and a large Immune response, Figure 4B, D, Tables 5, 6 and Supplementary Figure 4.…”

Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS

“…We have recently mapped the transcriptomic changes occurring in human microglia during amyloid-b pathology using a xenotransplantation mouse model (24). To shed light on whether C9orf72 HRE modifies the microglial phenotype, we performed a gene enrichment analysis and mapped those transcriptomic signatures in our dataset).…”