|Exploration of molecular mechanism of the retina aging
|Lin, Bin (SO)
|FHSS Faculty Distinguished Thesis Award (2020/21)
Eye -- Aging
Hong Kong Polytechnic University -- Dissertations
|School of Optometry
|xviii, 183 pages : color illustrations
|Progressive structural and functional decline in the brain is observed during normal aging process. It is important to study the mechanisms that contribute to aging-related alterations in the brain to slow down brain aging process. However, the basic mechanisms of brain aging still remain unclear. Systematic factors have been reported to regulate age-related alterations and contribute to cognitive decline in the aging brain by initiating a series of intracellular or extracellular signal pathways. However, such systematic factors associated with normal aging remain poorly understood. Therefore, it would be critical to identify such circulating factors for inhibiting the effects of the systemic pro-aging factors in normal aging brain. In visual system, age-related morphological and functional decline had been reported in aged retinas. As the retinais known as the extension of the brain, here we used the retina as a window to identify systematic pro-aging factors by observing morphological and functional alterations in the retina aging process. We initially found that heterochronic parabiosis or old plasma treatment induced the activation of microglia and astrocytes, and elicited the ectopic dendritic sprouting of rod bipolar and horizontal cells and the visual function decline in the retina of young mice, confirming that systematic factors could contribute to retina aging process. Our proteomic analysis revealed that TPM1, an actin-associated protein tropomysion 1 (TPM1), was a potential systematic factor underlying age-related deficits in the retina of aged mice. Retro-obital injection with recombinant TPM1 protein in young mice recapitulated the similar effects of old plasma on young mice, whereas administration with anti-TPM1 antibody ameliorated the age-related impairments in aged retinas, confirming that systematic TPM1 had a direct effect on retina aging process. Furthermore, we demonstrated that systematic TPM1 accumulation induced endogenous TPM1 expression in aged retinas via the FABP5/NF-κB signaling pathway and the AC/cAMP/PKA signaling pathway to exacerbate age-related deficits. Additionally, we found that cyclooxygenase (COX)-1 and COX-2, two key enzymes that convert arachidonic acid into proinflammatory prostaglandins, regulated TPM1 expression in aged retinas. Interestingly, we found that TPM1 elevation and age-related structural and functional decline which were observed in normal aging retinas were also presented in young mouse models of Alzheimer's disease, indicating that TPM1 might play a pro-aging role in age-related neurodegenerative disease. Together, our data suggest that TPM1 may be therapeutically targeted for combating the effects of aging in old age.
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