BRIEF RESEARCH REPORT article
Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
This article is part of the Research TopicGlial cells as gatekeepers of neurodegeneration and metabolic diseasesView all articles
Unmasking Early Microglial Remodeling in an Alzheimer's Disease Mouse Model
Provisionally accepted
Priyanka Saminathan
Sara McArdle*
Maija Corey
Namratha NadigCamille Fang
Alicia Gibbons
Mahati Rayadurgam
Sonia Sharma*- La Jolla Institute for Immunology, San Diego, United States
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Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across ~11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.
Keywords: microglia morphometry, image segmentation, QuPath, Neuroinflammation, Alzheimer's disease, Iba1 and CD68 quantification, Morphological remodeling, Hippocampus
Received: 08 Oct 2025; Accepted: 27 Nov 2025.
Copyright: © 2025 Saminathan, McArdle, Corey, Nadig, Fang, Gibbons, Rayadurgam and Sharma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sara McArdle
Sonia Sharma
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