Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes

Abstract

Background Amongst risk alleles associated with late-onset Alzheimer’s disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. Methods We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aβ and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. Results We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aβ and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aβ and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec-10, the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. Conclusions Using scRNA-Seq in mouse models bearing amyloid-β and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aβ and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aβ and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets.

S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice

“…CITE-Seq did not reveal a subpopulation unique to the K18+P301L model, but we did observe a modest increase in the DAM population, consistent with other single-cell RNA sequencing studies in other tauopathy models, such as TE4 mice (P301S expressing human APOE4) and Tau4RΔK-AP mice (Chen et al, 2023; Kim et al, 2022). In line with the Tau4RΔK-AP mice study, the increase of the DAM subpopulation was only observed at late stages of hyperphosphorylated tau spreading (Kim et al, 2022). Furthermore, there was no one-on-one relationship between DAM emergence and hyperphosphorylated tau load.…”

“…Recent studies suggest that microglial activation can accelerate tau aggregation and behavioural abnormalities in a hTau mouse model (Bhaskar et al, 2010; Chen et al, 2023; Gratuze et al, 2023; Sierksma et al, 2020; C. Wang et al, 2022), and that the accumulation of senescent microglia contributes to tau aggregation in a hTau.P301S (PS19) mouse model (Bussian et al, 2018). While there have been some studies investigating microglial subpopulations in models of tauopathy and in human brains (Chen et al, 2023; Gerrits et al, 2021; Kim et al, 2022), there is a lack of a comprehensive understanding of the influence of tau on microglia and the evolution of microglial heterogeneity during tau pathology progression. Furthermore, considering that microglia are long-lived cells, and that the most important risk factor for neurodegeneration is age, it can be expected that age-associated changes in microglia prime for pathology as well (Yoo & Kwon, 2022).…”

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…The association between microglia, astrocyte with AD pathologies has not been fully understood. Aβ and tau pathologies have been shown to exert distinct influences and induce disease stage-specific microglial subtypes (25, 35). Microglial activation measured by PET using tracer for translocator protein is found associated with AD amyloid and tau pathology (58).…”

Transcriptomic Profiling of Thyroid Eye Disease Orbital Fat Demonstrates Differences in Adipogenicity and IGF-1R Pathway

“…Matrix files generated from the Cellranger run were used for subsequent analysis as described previously (18, 23). Briefly, Seurat V3 (24) was used to perform downstream analysis, only including cells with more than 500 genes, and 1000 UMI, to process control and treated samples separately.…”