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Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination. [ABSTRACT FROM AUTHOR]

Background: Progressive retinal ganglion cell (RGC) dysfunction and death are common characteristics of retinal neurodegenerative diseases. Recently, hydroxycarboxylic acid receptor 1 (HCA1R, GPR81) was identified as a key modulator of mitochondrial function and cell survival. Thus, we aimed to test whether activation of HCA1R with 3,5-Dihydroxybenzoic acid (DHBA) also promotes RGC survival and improves energy metabolism in mouse retinas. Methods: Retinal explants were treated with 5 mM of the HCA1R agonist, 3,5-DHBA, for 2, 4, 24, and 72 h. Additionally, explants were also treated with 15 mM of L-glutamate to induce toxicity. Tissue survival was assessed through lactate dehydrogenase (LDH) viability assays. RGC survival was measured through immunohistochemical (IHC) staining. Total ATP levels were quantified through bioluminescence assays. Energy metabolism was investigated through stable isotope labeling and gas chromatography-mass spectrometry (GC-MS). Lactate and nitric oxide levels were measured through colorimetric assays. Results: HCA1R activation with 3,5-DHBAincreased retinal explant survival. During glutamate-induced death, 3,5-DHBA treatment also increased survival. IHC analysis revealed that 3,5-DHBA treatment promoted RGC survival in retinal wholemounts. 3,5-DHBA treatment also enhanced ATP levels in retinal explants, whereas lactate levels decreased. No effects on glucose metabolism were observed, but small changes in lactate metabolism were found. Nitric oxide levels remained unaltered in response to 3,5-DHBA treatment. Conclusion: The present study reveals that activation of HCA1R with 3,5-DHBA treatment has a neuroprotective effect specifically on RGCs and on glutamate-induced retinal degeneration. Hence, HCA1R agonist administration may be a potential new strategy for rescuing RGCs, ultimately preventing visual disability. [ABSTRACT FROM AUTHOR]

Aims/Purpose: The aim of the study is to evaluate energy metabolism and retinal tissue survival in retinal explants in a murine model of AD (TgSwDI) during aging. Methods: The 7‐, 12‐ and 24‐month‐old TgSwDI mouse model was compared with age‐matched wild‐type (WT) mice. Characterization of the mouse model was assessed by Aβ plaques staining. Cell viability was evaluated by lactate dehydrogenase (LDH) assay of retinal explants at 4 and 24 h of incubation with culture media. Retinal ganglion cell (RGC) survival was quantified by RBPMS staining in 7‐month‐old mice. Glucose metabolism was analysed by gas chromatography mass spectrometry (GC–MS) using uniformly labelled glucose by incubating whole retinas for 30 min with glucose in 7‐month‐old mice. And lactate, produced by glycolysis, was evaluated by the lactate assay in 7‐month‐old mice. Results: The presence of Aβ plaques and vascularization was detected in the retinas of TgSwDI mice, whereas they were not found in the retinas of control mice. At 7 months, the viability of retinal explants was reduced in the TgSwDI model compared to the age‐matched WT model using the LDH assay. Compared to controls, RGC survival in the TgSwDI model tended to decrease. We performed GC–MS to evaluate glucose metabolism and observed no difference between the TgSwDI and WT groups. Lactate production showed no significant differences between the groups. Conclusions: The presence of Aβ plaques was detected in the retinas of the TgSwDI model, indicating that it is a good model for studying the retina in AD. Retinal tissue viability was altered at different ages in the TgSwDI model, and RGC survival was also reduced in the AD model, substantiating that AD affect the retina. We did not detect any differences between WT and TgSwDI groups in energy metabolism, implying that alterations in retinal tissue and cell survival may be related to other pathways. Further studies are needed to explore this, ultimately providing novel insight to address visual function affected by AD. [ABSTRACT FROM AUTHOR]

* Shared co‐author. Purpose: Previous cerebral studies of Alzheimer's disease (AD) have provided evidence for a neuronal metabolic dysfunction, which precede the cognitive decline. Since the retina is one of the most energy demanding tissues in the body and considered an extension of the brain due to its origin from the neural tissue, we speculate whether dysfunctional energy metabolism is present in AD models. Thus, the aim of the study is to evaluate energy metabolism and tissue survival in retinal explants in a murine model of AD (TgSwDI) during aging. Methods: The 8‐, 12‐, and 24‐month‐old TgSwDI mouse model was compared with age‐matched wild‐type (WT) mice. Tissue survival was assessed by lactate dehydrogenase (LDH) viability assays of retinal explants at 2, 4 and 24 hours of incubation with culture media. Total ATP levels were quantified by bioluminescence assays to assess energy metabolism in TgSwDI mice. Results: Retinal explant survival was reduced in the TgSwDI model compared to the age‐matched WT model with LDH assay at 8 months. The 8‐month‐old AD TgSwDI mice showed a tendency to decrease in total ATP levels after 2 hours of retinal explant incubation (p = 0.07). Conclusions: Retinal tissue survival is impaired in the TgSwDI model during various ages, and tendencies of decreased retinal ATP levels were established at 8 months, implying disrupted retinal energy metabolism similar to changes observed in the AD brain. [ABSTRACT FROM AUTHOR]