TY - JOUR
T1 - Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes
AU - Kim, Dong Won
AU - Tu, Kevin J.
AU - Wei, Alice
AU - Lau, Ashley J.
AU - Gonzalez-Gil, Anabel
AU - Cao, Tianyu
AU - Braunstein, Kerstin
AU - Ling, Jonathan P.
AU - Troncoso, Juan C.
AU - Wong, Philip C.
AU - Blackshaw, Seth
AU - Schnaar, Ronald L.
AU - Li, Tong
N1 - Funding Information:
We thank the Transcriptomics and Deep Sequencing Core (Johns Hopkins) for the sequencing of scRNA-Seq libraries and the Johns Hopkins ADRC Neuropathology Core for brain tissues.
Funding Information:
This work was supported in part by the Maryland Stem Cell Research Fund (2019-MSCRFF-5124) to DWK, grants from the National Institute of Aging (R56AG068089) to RLS and TL, (R21AG073710) to TL, and the National Institute of Neurological Disorders and Stroke (R61NS115161 and R01NS095969) to PCW.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Alzheimer’s disease (AD)
KW - Amyloid-β (Aβ)
KW - Microglia
KW - Sialic acid-binding immunoglobulin-type lectin (Siglec)
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85144281297&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144281297&partnerID=8YFLogxK
U2 - 10.1186/s13024-022-00589-x
DO - 10.1186/s13024-022-00589-x
M3 - Article
C2 - 36536457
AN - SCOPUS:85144281297
SN - 1750-1326
VL - 17
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 83
ER -