# Retinal Degeneration in Alzheimer’s Disease 5xFAD Mice Fed DHA-Enriched Diets

## TL;DR

This study shows that DHA-rich diets can protect the retina in Alzheimer's mice, suggesting the retina could be a useful indicator for tracking the disease.

## Contribution

The study demonstrates that DHA supplementation from non-fish sources can protect retinal integrity in Alzheimer’s disease models.

## Key findings

- DHA supplementation from fish oil or DHASCO oil increased retinal ganglion cell layer density in 5xFAD mice.
- Fish oil reduced TAU protein immunostaining in retinal layers compared to controls.
- No β-amyloid plaques or IBA1 staining was observed in the retinas of 5xFAD mice.

## Abstract

The adequate intake of docosahexaenoic acid (DHA, 22:6n − 3) is important for preventing cognitive decline and assuring brain optimal function, especially in early Alzheimer’s disease (AD) stages.

The pivotal role of DHA for protecting retinal integrity in AD remains elusive.

The neuroprotective effects of DHA supplementation in 5xFAD mice were found in the retina, from both fish oil and DHASCO commercial oil, concerning the retinal layer thickness, TAU protein aggregates, and retinal ganglion cell layer density, respectively.

These retinal alterations promoted by dietary DHA reinforce the retina as a valuable site for detecting and monitoring AD.

Alzheimer’s disease (AD) is marked by cognitive decline, and also by retinal degeneration. Having in mind that docosahexaenoic acid (DHA, 22:6n − 3) is a safe, low-cost, and pivotal fatty acid for brain health and sustained cognitive function, this study exploits environmentally friendly non-fish sources as potential dietary supplements enriched with DHA to prevent or reverse AD. Forty 5xFAD transgenic male mice, aged five weeks old, were randomly distributed by five body weight-matched dietary groups (with eight animals each) and fed isocaloric diets based on the AIN-93M standard formulation for rodents for 6 months. Except for the control feed (without supplementation), each diet contained a modified lipidic fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA, 18:3n − 3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n − 3)); (3) Schizochytrium sp. microalga oil (Schizo, with 40% of DHA); and (4) commercial DHASCO (DHASCO, with 70% of DHA). The aim of this study was to measure retinal neural layer thickness, calculate ganglion cell layer (GCL) density, and assess retinal injury by means of immunohistochemical staining for β-amyloid plaques deposition, TAU protein levels, and IBA1, as hallmark features of AD progression, in order to elucidate the effects of different dietary DHA treatments in Alzheimer’s retinas. Although no statistical differences were observed across retinal layer thicknesses depending on the diet (p > 0.05), there was a consistent pattern for slightly increased retinal thickness in 5xFAD mice fed fish oil relative to the others for the measurement of total layers, in general and for the inner segment/outer segment layer, the outer nuclear layer, the outer plexiform layer, the inner nuclear layer, and the inner plexiform layer, in particular. The ganglion cell layer (GCL) density was increased in 5xFAD mice fed the DHASCO oil diet relative to the control (p < 0.05), suggesting a benefit of DHA supplementation on the number of viable ganglion cells. No positive staining was observed for β-amyloid plaques deposition or the neuroinflammatory marker, IBA1, corroborating previous findings in human AD retinas. Conversely, the internal retinal layers showed intense TAU immunostaining. Immnunostained TAU area was significantly reduced in 5xFAD mice fed a fish oil diet compared to control (p < 0.05), although the number of TAU-positive cells did not differ across diets (p > 0.05). The retinal protected integrity derived from the benefits of DHA supplementation found, either from fish oil or DHASCO oil, underscores the potential of retinal biomarkers as non-invasive indicators of cognitive decline and overall brain health, opening new avenues for investigating AD pathophysiology in the retina.