Dynamic remodeling of microglial responses in Alzheimer's disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation.
- 1School of Management, Qilu Medical University, Zibo, Shandong, China.
- 2College of Sport and Health, Shandong Sport University, Jinan, China.
- 3Department of Neurology, Zibo 148 Hospital, Zibo, Shandong, China.
Abstract
Alzheimer's disease (AD) is characterized by progressive neuroinflammation involving microglia whose functional responses extend far beyond the classical M1/M2 framework and form a dynamically heterogeneous continuum. Here, we review recurrent disease-associated microglia (DAM) states and transcriptional programs, including DAM-associated, interferon-responsive, cytokine-responsive, proliferative, antigen-presentation-associated, and lipid-associated features, emphasizing that these labels do not necessarily represent fixed or mutually exclusive cellular subtypes. Across AD progression, the relative engagement and functional consequences of these programs vary according to Aβ and tau burden, local microenvironment, genetic background, metabolic status, and disease stage. DAM-associated programs may support phagocytosis and plaque containment in some contexts, whereas persistent inflammatory and metabolic stress can increase lipid dysregulation, mitochondrial dysfunction, impaired phagocytic competence, and inflammatory signaling in subsets of microglia. Microglia also exert bidirectional effects on tau pathology. Core AD risk pathways, including TREM2 and APOE, together with immunometabolic remodeling, shape microglial plasticity in a context-dependent manner. We discuss the implications of this dynamic framework for stage- and state-aware therapeutic strategies and highlight the need to integrate single-cell, spatial, and multi-omic approaches to resolve microglial trajectories and functional states in human AD.
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BibTeX
@article{han2026dynamic,
title = {{Dynamic remodeling of microglial responses in Alzheimer's disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation.}},
author = {Simin Han and Shanshan Wang and Jingjing Liu and Xulin Liu and Qinglu Wang and Chang Meng},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1929282},
url = {https://europepmc.org/article/MED/42947965},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic remodeling of microglial responses in Alzheimer's disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation.
AU - Simin Han
AU - Shanshan Wang
AU - Jingjing Liu
AU - Xulin Liu
AU - Qinglu Wang
AU - Chang Meng
PY - 2026
DA - 2026/10/13
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1929282
UR - https://europepmc.org/article/MED/42947965
AB - Alzheimer's disease (AD) is characterized by progressive neuroinflammation involving microglia whose functional responses extend far beyond the classical M1/M2 framework and form a dynamically heterogeneous continuum. Here, we review recurrent disease-associated microglia (DAM) states and transcriptional programs, including DAM-associated, interferon-responsive, cytokine-responsive, proliferative, antigen-presentation-associated, and lipid-associated features, emphasizing that these labels do not necessarily represent fixed or mutually exclusive cellular subtypes. Across AD progression, the relative engagement and functional consequences of these programs vary according to Aβ and tau burden, local microenvironment, genetic background, metabolic status, and disease stage. DAM-associated programs may support phagocytosis and plaque containment in some contexts, whereas persistent inflammatory and metabolic stress can increase lipid dysregulation, mitochondrial dysfunction, impaired phagocytic competence, and inflammatory signaling in subsets of microglia. Microglia also exert bidirectional effects on tau pathology. Core AD risk pathways, including TREM2 and APOE, together with immunometabolic remodeling, shape microglial plasticity in a context-dependent manner. We discuss the implications of this dynamic framework for stage- and state-aware therapeutic strategies and highlight the need to integrate single-cell, spatial, and multi-omic approaches to resolve microglial trajectories and functional states in human AD.
SN - 2296-634X
ER -