Morpho-Functional Characterization and miRNA Profiling of the Retina in the 5xFAD Murine Model of Alzheimer's Disease.

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.