Abstract
Visual changes are some of the earliest symptoms that patients with Alzheimer’s disease (AD) experience. 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 models. 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 demands. We thus hypothesized that energy metabolism might be compromised in the AD retina similarly to what has been observed in the AD brain. To address this question, we explored cellular alterations and retinal metabolic activity in the 5 × FAD mouse model of AD. We used 8-month-old female 5 × FAD 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 5 × FAD 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 5 × FAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5 × FAD 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. 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.
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All data of this study are available upon request to the corresponding authors.
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The authors thank Laboratory Technician Charlotte Taul Brændstrup for skillful assistance in this study.
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The work was supported by the BRIDGE—Translational Excellence Programme funded by the Novo Nordisk Foundation (Grant agreement no. NNF18SA0034956), Hørslev-Fonden (203866-MAS/mbs1), and Beckett Fonden (19-2-4285).
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MK and BIA developed the concept and hypothesis for the study. Material preparation, data collection and analysis were equally performed by ALMT and BS-M. EWW, JVA and ZAM provided support with the maintenance of mouse colonies and sample preparation. JH supervised the immunohistochemistry analysis of retina whole-mounts and assisted with image acquisition. MK, BIA, JVA, RV, and KKF critically revised the work. The first draft of the manuscript was written by ALMT and BS-M and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Tams, A.L.M., Sanz-Morello, B., Westi, E.W. et al. Decreased Glucose Metabolism and Glutamine Synthesis in the Retina of a Transgenic Mouse Model of Alzheimer’s Disease. Cell Mol Neurobiol 42, 291–303 (2022). https://doi.org/10.1007/s10571-021-01126-y
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DOI: https://doi.org/10.1007/s10571-021-01126-y