Purpose

Visual changes are some of the earliest symptoms that patients with Alzheimer’s disease (AD) experience1. Pathophysiological processes such as amyloid-β plaque formation, vascular changes, neuroinflammation, and loss of retinal ganglion cells (RGCs) have been detected in the retina of AD patients and animal models1. However, little is known about the molecular processes that underlie retinal neurodegeneration in AD. The cellular architecture and constant sensory activity of the retina impose high metabolic demands2. We thus hypothesized that energy metabolism might be compromised in the AD retina similarly to what has been observed in the AD brain3.

Methods/ Results

To address this question, we explored cellular alterations and retinal metabolic activity in the 5xFAD mouse model of AD. We used 8-months old female 5xFAD mice, in which the AD-related pathology has been shown to be apparent. We observed that RGC density is selectively affected in the retina of 5xFAD mice. To map retinal metabolic activity, we incubated isolated retinal tissue with [U-13C]glucose and analyzed tissue extracts by gas chromatography-mass spectrometry. We found that the retinas of 5xFAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5xFAD retinas but no changes in the expression of markers of Müller glia, the main glial cell type responsible for glutamate uptake and glutamine synthesis in the retina.

Conclusions These findings suggest that AD presents with metabolic alterations not only in the brain but also in the retina that may be detrimental to RGC activity and survival, potentially leading to the visual impairments that AD patients suffer. Chiquita, S. et al. The Retina as a Window or Mirror of the Brain Changes Detected in Alzheimer’s Disease: Critical Aspects to Unravel. Molecular Neurobiology vol. 56 5416–5435 (2019). Oesch, N. W., Wade Kothmann, W. & Diamond, J. S. Illuminating synapses and circuitry in the retina. Current Opinion in Neurobiology vol. 21 238–244 (2011). Andersen, J. V. et al. Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 148, (2021).