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Early and progressive retinal microglial changes in APPNL-F/NL-F mouse model of Alzheimer's disease revealed by an
Lidia Sánchez-Puebla1,2,3, Inés López-Cuenca1,2,4, Miguel A Sánchez-Puebla5
1Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid, Madrid, Spain.
Abstract:
Alzheimer's disease (AD) is characterized by the accumulation of misfolded proteins that trigger neuroinflammation and neuronal loss. The retina, as an extension of the central nervous system, mirrors these pathological processes and represents a potential biomarker. Microglial activation, a key component of neuroinflammation, can be morphologically assessed through automated image analysis. This study performed a quantitative and morphological analysis of retinal microglia in the APPNL-F/NL-F mouse model of AD across aging (6-20 months) and comparing them with age-matched C57BL/6 J controls using an automated image analysis software. A cross-sectional design was applied to 72 mice (36 APPNL-F/NL-F and 36 WT). Retinas samples were processed by Iba-1 immunohistochemistry. Quantified parameters included cell number, soma size, arborization area, skeletonization, fluorescence intensity, and Feret's Diameter Ratio across OS, OPL, IPL, and NFL/GCL layers. Image analysis was performed using a custom automated system, called MorphoSomas, specifically developed for the comprehensive morphological assessment of microglia. Age-dependent changes were observed in both groups. WT mice showed a later and more gradual activation pattern, whereas APPNL-F/NL-F mice exhibited early activation from 6 months, characterized by increased cell number and soma size, followed by reductions in arborization and skeletonization, indicating progressive activation. The automated system allowed precise and reproducible assessment, highlighting significant differences between groups and retinal layers. In conclusion, retinal microglia in APPNL-F/NL-F mice exhibit early and biphasic activation followed by signs of dysfunction, reflecting AD neuropathology. Automated analysis enhances objectivity and efficiency in morphological studies. These findings support the retina as a promising, non-invasive biomarker for early AD detection.
Insights
Retinal microglia in Alzheimer's disease (AD) models show early activation and dysfunction, mirroring brain pathology. Automated analysis of these retinal changes offers a promising, non-invasive biomarker for early AD detection.
Area of Science:
- Neuroscience
- Ophthalmology
- Biomarker Discovery
Background:
- Alzheimer's disease (AD) involves neuroinflammation and neuronal loss, with the retina potentially reflecting these central nervous system changes.
- Microglial activation, a key neuroinflammatory marker, can be assessed morphologically, particularly in the retina.
Purpose of the Study:
- To quantitatively and morphologically analyze retinal microglia in an AD mouse model (APPNL-F/NL-F) across aging.
- To compare microglial changes in AD mice with age-matched controls (C57BL/6 J) using automated image analysis.
- To evaluate the retina as a potential non-invasive biomarker for early AD detection.
Main Methods:
- A cross-sectional study involving 72 mice (36 APPNL-F/NL-F, 36 WT) aged 6-20 months.
- Iba-1 immunohistochemistry on retinal samples followed by automated image analysis using the MorphoSomas system.
- Quantification of microglial parameters including cell number, soma size, arborization, skeletonization, and Feret's Diameter Ratio across retinal layers.
Main Results:
- APPNL-F/NL-F mice showed early microglial activation from 6 months, with increased cell number and soma size.
- Progressive activation in APPNL-F/NL-F mice was indicated by reduced arborization and skeletonization, suggesting dysfunction.
- Age-dependent changes were observed in both groups, with WT mice exhibiting a more gradual activation pattern.
Conclusions:
- Retinal microglia in the APPNL-F/NL-F mouse model display early, biphasic activation and subsequent dysfunction, mirroring AD neuropathology.
- Automated morphological analysis of retinal microglia provides objective and efficient assessment.
- These findings support the retina's potential as a non-invasive biomarker for early Alzheimer's disease diagnosis.
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