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Morpho-Functional Characterization and miRNA Profiling of the Retina in the 5xFAD Murine Model of Alzheimer's Disease
Lorenzo Guidotti1, Martina Lucchesi1, Eleonora Daghini1
1Department of Biology, University of Pisa, Pisa, Italy.
Purpose:
Alzheimer's disease (AD) induces changes in retinal structure/function, making the retina a suitable platform to study the molecular mechanisms of the disease. Dysregulation of some microRNAs (miRNAs) has also been found in AD pathogenesis. Here, we used the 5xFAD mouse to expand our knowledge on structural, functional, and molecular retinal alterations and to elucidate the retinal miRNA profile in this model of AD.
Methods:
The 5xFAD mice at 3, 6, or 9 months of age, were used. Retinal function was evaluated with electroretinogram (ERG) and the Prusky water maze test. Retinal structure was investigated by optical coherence tomography. Molecular analyses included immunohistochemistry, Western blot, and ELISA. Retinal miRNAs were profiled and deregulated miRNAs were validated by qRT-PCR.
Results:
Starting from 6 months, the 5xFAD mice showed altered ERG and visual acuity. The inner plexiform layer became thicker whereas the retinal ganglion cell (RGC) layer became thinner. In the RGC layer, the accumulation of amyloid beta was concomitant with RGC apoptosis, whereas tau protein phosphorylation was increased. Inflammatory processes were also activated and microgliosis became apparent. Five deregulated miRNAs were identified, four of which were validated. Two of these miRNAs were related to AD and involved in gene expression relevant to retinal function.
Conclusions:
The present findings confirm and expand our knowledge of the retinal disease in 5xFAD mice, and highlight that neuroinflammation, oxidative stress, and microgliosis participate in AD pathogenesis. The relationship between deregulated miRNAs and AD progression may open the field to miRNA-based strategies to slow down retinal dysfunction in AD.
Insights
Alzheimer's disease causes retinal changes in 5xFAD mice, including altered function and structure. Specific microRNAs (miRNAs) were identified as potential biomarkers for disease progression.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Alzheimer's disease (AD) affects retinal structure and function, offering insights into disease mechanisms.
- MicroRNA (miRNA) dysregulation is implicated in Alzheimer's disease pathogenesis.
Purpose of the Study:
- Investigate structural, functional, and molecular retinal changes in the 5xFAD mouse model of AD.
- Elucidate the retinal miRNA profile in 5xFAD mice to identify potential AD biomarkers.
Main Methods:
- Evaluated retinal function using electroretinogram (ERG) and Prusky water maze.
- Assessed retinal structure via optical coherence tomography.
- Conducted molecular analyses including immunohistochemistry, Western blot, ELISA, and miRNA profiling (qRT-PCR).
Main Results:
- 5xFAD mice showed altered ERG and visual acuity from 6 months.
- Observed thickening of the inner plexiform layer and thinning of the retinal ganglion cell (RGC) layer.
- Found amyloid beta accumulation, RGC apoptosis, increased tau phosphorylation, neuroinflammation, and microgliosis.
- Identified five deregulated miRNAs, with two linked to AD pathogenesis and retinal function.
Conclusions:
- Retinal alterations in 5xFAD mice confirm and expand knowledge of AD-related retinal disease.
- Neuroinflammation, oxidative stress, and microgliosis are key in AD pathogenesis.
- miRNA dysregulation offers potential for therapeutic strategies to mitigate retinal dysfunction in AD.
