Abstract
Age-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.
Highlights
Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder, whose onset precedes the disease’s symptoms and diagnosis
We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target suppressor of cytokine signaling 1 (SOCS-1)
In light of the reported link between AD and retinal degeneration phase (15-month-old mice), significantly downregulated miRNAs associated with age-related macular degeneration (AMD) [10] and to identify useful biomarkers of such as miR-23a and miR-27a could act as positive regulators of disease progression, we analyzed the expression of a specific set the TNFRSF10B receptor and FADD, likely promoting their of miRNAs, involved in both disease conditions, in retina extracts detrimental effects on the retina
Summary
Alzheimer’s Disease (AD) is an age-related neurodegenerative disorder, whose onset precedes the disease’s symptoms and diagnosis. AD-associated neuroinflammation and considering that the this group of miRNAs, miR-155-5p, miR-126-3p and retina is an integral part of the central nervous system miR-23a-3p revealed that these miRNAs target genes originating from the neural tube, in the present study, we belonging to the TNF-related apoptosis-inducing ligand investigated the expression of a focused set of miRNAs, linked to (TNFSF10)-mediated apoptotic signaling pathway Looking at the time-dependent pattern of expression of miRNAs obtained in 3xTg-AD mice, we observed that in young mice
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