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Updated: May 28, 2026
Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Early Regional Microglial Remodelling in the Hippocampus of the AppNL-G-F Alzheimer's Model
Ryan J Bevan1, Jessica F Minett2, Alice L Smith1
1UK Dementia Research Institute at Cardiff University, Cardiff University, Cardiff, UK.
Aims:
Microglia undergo profound structural and functional changes during Alzheimer's disease, yet the earliest stages of morphological remodelling that occur prior to amyloid deposition remain poorly defined. We hypothesised that microglia in the hippocampus of AppNL-G-F mice would exhibit early, region-specific structural adaptations before local plaque formation, reflecting an initial phase of disease-associated structural remodelling.
Methods:
Two-month-old AppNL-G-F and wildtype mice were examined using high-resolution confocal microscopy of Iba1-labelled microglia in the dorsal CA1 apical field. Automated three-dimensional reconstructions were generated in Imaris, and quantitative morphometric analyses quantified cell density, Iba1 coverage, process topology and Sholl-based arbor complexity. Statistical analyses were performed using linear mixed-effects models incorporating sex as a fixed factor in all analyses.
Results:
Microglial density and total Iba1 coverage were unaffected in AppNL-G-F mice at this age. In contrast, Sholl analysis revealed significant genotype-dependent reductions in process intersections and total process length, accompanied by reduced individual-cell territorial coverage, indicating an early contraction of the surveillance arbor independent of cell number.
Conclusions:
These findings demonstrate that hippocampal microglia in AppNL-G-F mice undergo an early, coordinated structural remodelling before local amyloid deposition becomes apparent. This preplaque adaptation defines an early structural remodelling of hippocampal microglia prior to evident local amyloid deposition, providing new insight into the earliest structural adaptations associated with neuroimmune engagement in AD pathogenesis.
Insights
Microglia in Alzheimer's disease models show early structural changes before amyloid plaques form. These findings reveal pre-plaque microglial adaptations in the hippocampus.
Area of Science:
- Neuroscience
- Immunology
- Alzheimer's Disease Research
Background:
- Microglia, the brain's immune cells, undergo significant changes in Alzheimer's disease (AD).
- The earliest microglial structural changes preceding amyloid deposition are not well understood.
- Understanding these early changes is crucial for identifying therapeutic targets in AD.
Purpose of the Study:
- To investigate early, region-specific microglial structural adaptations in the hippocampus of AppNL-G-F mice before amyloid plaque formation.
- To test the hypothesis that microglia exhibit pre-plaque structural remodeling as an initial disease-associated response.
Main Methods:
- High-resolution confocal microscopy was used to examine Iba1-labeled microglia in the dorsal CA1 apical field of 2-month-old AppNL-G-F and wildtype mice.
- Automated 3D reconstructions and quantitative morphometric analyses assessed cell density, Iba1 coverage, process topology, and Sholl-based arbor complexity.
- Linear mixed-effects models were employed for statistical analysis, including sex as a fixed factor.
Main Results:
- Microglial density and Iba1 coverage remained unchanged in AppNL-G-F mice at this early stage.
- Sholl analysis indicated significant genotype-dependent reductions in process intersections and total process length.
- A decrease in individual-cell territorial coverage was observed, suggesting an early contraction of the microglial surveillance arbor independent of cell number.
Conclusions:
- Hippocampal microglia in AppNL-G-F mice exhibit early, coordinated structural remodeling prior to the appearance of local amyloid deposition.
- This pre-plaque adaptation highlights an early phase of neuroimmune engagement in AD pathogenesis.
- These findings offer novel insights into the initial structural adaptations of microglia in the context of AD.
