Stepwise Upregulation of Microglial Genes through the Slow Progression of Amyloid Pathology in Alzheimer’s Disease Model Mice
Abstract
The mechanistic role of microglial activation in Alzheimer’s disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of AppNL-F knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in AppNL-F mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer’s disease.
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BibTeX
@article{shirotani2026stepwise,
title = {{Stepwise Upregulation of Microglial Genes through the Slow Progression of Amyloid Pathology in Alzheimer’s Disease Model Mice}},
author = {Keiro Shirotani and Daisuke Hatta and Kaori Watanabe and Takashi Saito and Takaomi C Saido and Nobuhisa Iwata},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = sep,
doi = {10.1248/bpb.b26-00310},
url = {https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00310/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Stepwise Upregulation of Microglial Genes through the Slow Progression of Amyloid Pathology in Alzheimer’s Disease Model Mice
AU - Keiro Shirotani
AU - Daisuke Hatta
AU - Kaori Watanabe
AU - Takashi Saito
AU - Takaomi C Saido
AU - Nobuhisa Iwata
PY - 2026
DA - 2026/09/01
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b26-00310
UR - https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00310/_article
AB - The mechanistic role of microglial activation in Alzheimer’s disease pathology is typically investigated using mouse models with aggressive amyloid accumulation, leaving the dynamics of microglial responses under the relatively slow deposition of amyloid-β (Aβ) characteristic of the early stages of the disease poorly understood. In this study, we examined microglial gene expression in the brains of AppNL-F knock-in mice, which gradually develop Aβ pathology in an aging-dependent manner without amyloid-β precursor protein overexpression. Quantitative PCR (qPCR) analysis revealed that microglial gene expression presents a stepwise activation pattern: early-induced genes increased at 12 months, whereas late-induced genes emerged at 18 months. Notably, neither group showed further induction at 24 months despite continued Aβ accumulation, indicating that microglial activation does not scale proportionally with the amyloid burden. Several canonical components of the disease-associated microglia program were not induced in AppNL-F mice, whereas a set of previously unrecognized microglial genes (Ly86, Snx20, and Pram1) was upregulated. The induction of these novel genes was preserved in the brains of Trem2 R47H knock-in mice, corroborating that the R47H variant exhibits only mild, if any, phenotype. Immunoblotting of selected proteins confirmed these qPCR-based findings. Together, these results reveal a stepwise mode of microglial gene activation under slow amyloid progression and identify novel genes that may be relevant to the early stages of Alzheimer’s disease.
SN - 1347-5215
SN - 0918-6158
ER -