TY - JOUR

T1 - Decreased Glucose Metabolism and Glutamine Synthesis in the Retina of a Transgenic Mouse Model of Alzheimer's Disease

AU - Tams, Anna Luna Mølgaard

AU - Sanz-Morello, Berta

AU - Westi, Emil Winther

AU - Mouhammad, Zaynab Ahmad

AU - Andersen, Jens Velde

AU - Freude, Kristine Karla

AU - Vohra, Rupali

AU - Hannibal, Jens

AU - Aldana, Blanca Irene

AU - Kolko, Miriam

N1 - Funding Information: The authors thank Laboratory Technician Charlotte Taul Brændstrup for skillful assistance in this study. Funding Information: 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). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2022

Y1 - 2022

N2 - Visual changes are some of the earliest symptoms that patients with Alzheimer's disease (AD) experience. Pathophysiological processes such as amyloid-beta 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 x FAD mouse model of AD. We used 8-month-old female 5 x 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 x FAD mice. To map retinal metabolic activity, we incubated isolated retinal tissue with [U-C-13] glucose and analyzed tissue extracts by gas chromatography-mass spectrometry. We found that the retinas of 5 x FAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5 x FAD retinas but no changes in the expression of markers of Muller 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.

AB - Visual changes are some of the earliest symptoms that patients with Alzheimer's disease (AD) experience. Pathophysiological processes such as amyloid-beta 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 x FAD mouse model of AD. We used 8-month-old female 5 x 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 x FAD mice. To map retinal metabolic activity, we incubated isolated retinal tissue with [U-C-13] glucose and analyzed tissue extracts by gas chromatography-mass spectrometry. We found that the retinas of 5 x FAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5 x FAD retinas but no changes in the expression of markers of Muller 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.

KW - Retina

KW - Alzheimer's disease

KW - Cellular metabolism

KW - Retinal ganglion cells

KW - Neurodegeneration

U2 - 10.1007/s10571-021-01126-y

DO - 10.1007/s10571-021-01126-y

M3 - Journal article

C2 - 34259962

VL - 42

SP - 291

EP - 303

JO - Cellular and Molecular Neurobiology

JF - Cellular and Molecular Neurobiology

SN - 0272-4340

IS - 1

ER -