Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression

Abstract

It is unknown whether specific microglia are selectively induced by amyloid-β(Aβ), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both Aβ and tau pathologies during Alzheimer's disease (AD). We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both Aβ and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

1-L Transcription in Alzheimer’s Disease

“…Mice do not express Siglec-8, but Siglec-F is a likely functional orthologue of Siglec-8. Siglec-F was upregulated on a subset of reactive microglia in models of neurodegeneration, and it was observed that Siglec-F is dependent on Aβ deposition at early AD stages [ 32 , 33 ].…”