Abstract
Background Emerging evidence from mouse models is beginning to elucidate the brain’s immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system.
Methods To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau.
Results Analysis of ∼181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 – the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models – in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation.
Conclusions Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.
Competing Interest Statement
JSY serves on the scientific advisory board for the Epstein Family Alzheimer's Research Collaboration. ALB has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave.
List of abbreviations
- AD
- Alzheimer’s disease
- ALS
- amyotrophic lateral sclerosis
- ALSP
- adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
- CAT
- Center for Advanced Technology
- cDC
- conventional dendritic cell
- CDR-SB
- Clinical Dementia Rating scale Sum of Boxes
- CNS
- central nervous system
- CSF
- cerebrospinal fluid
- dd
- droplet digital
- DEG
- differentially expressed gene
- FDR
- false discovery rate
- FTD
- frontotemporal dementia
- FTLD
- frontotemporal lobar degeneration
- IHG
- Institute for Human Genetics
- LFC
- log2 fold-change
- LPS
- lipopolysaccharide
- MAC
- Memory and Aging Center
- MCL
- Markov cluster algorithm
- NC
- nonclassical
- NK
- natural killer
- PBMCs
- peripheral blood mononuclear cells
- PCA
- principal component analysis
- PD
- Parkinson’s disease
- PET
- positron emission tomography
- QC
- quality control
- RIN
- RNA integrity number
- RT
- reverse transcription
- scRNA-seq
- single-cell RNA sequencing
- UCSF
- University of California, San Francisco
- UMAP
- uniform manifold approximation and projection