In Alzheimer's patients, cognitive and memory impairments are accompanied by visual disturbances linked to primary visual cortex dysfunction and retinal degeneration. Features of Alzheimer's disease (AD), such as amyloidogenesis, inflammation and vascular modifications propagate to the retina, as well as, to the brain. Therefore, the retina as a window to the brain may provide important clues to the understanding of AD pathogenesis. There is also a current trend for using the clinical, non-invasive imaging analyses of the retina in order to detect and diagnose AD in patients. Here, we investigated the cytokine TRAIL of the TNF family, which is involved in inflammatory/immune and angiogenic processes, and neurodegenerative events. TRAIL mediates stimuli noxious to neurons, such as amyloid-? (A?), ischemia, or trauma, all causing neuronal damage and death. Using a triple transgenic mouse model of AD (3xTg-AD mouse), which bears mutations in APP, PS1 and tau, and shows pathological signs resembling those of AD patients, we studied the pattern of AD-associated retinal degeneration, extending analysis to the retinal pigment epithelium (RPE) and choroid. They were examined deposition of amyloid-? and phospho-tau, TRAIL and its receptors, activated gliosis and microglia, cytokines and COX-2 expression and, finally, the hypoxia-induced angiogenic VEGF factor and apoptotic death. Importantly, pathological signs of 3xTg-AD retinal specimens were compared to those from 3xTg-AD mice that were subjected to a chronic treatment with an anti-TRAIL antibody for 15 months. The results show A? and phospho-tau deposits in the parenchyma and blood vessels of eye structures along with changes in TRAIL system, inflammation and vascular abnormalities, that were all prevented by the treatment with the neutralizing TRAIL antibody. We suggest that the 3xTg-AD mice have AD-associated signs of retinal degeneration and RPE/choroid dysfunction, and TRAIL is central to the aberrant modifications of these structures that benefit from anti-TRAIL treatment.
TRAIL and TRAIL neutralizing antibody in the retina and RPE/choroid of the 3xTg-AD mouse model of Alzheimer disease.
I Deidda;P Guarneri;
2015
Abstract
In Alzheimer's patients, cognitive and memory impairments are accompanied by visual disturbances linked to primary visual cortex dysfunction and retinal degeneration. Features of Alzheimer's disease (AD), such as amyloidogenesis, inflammation and vascular modifications propagate to the retina, as well as, to the brain. Therefore, the retina as a window to the brain may provide important clues to the understanding of AD pathogenesis. There is also a current trend for using the clinical, non-invasive imaging analyses of the retina in order to detect and diagnose AD in patients. Here, we investigated the cytokine TRAIL of the TNF family, which is involved in inflammatory/immune and angiogenic processes, and neurodegenerative events. TRAIL mediates stimuli noxious to neurons, such as amyloid-? (A?), ischemia, or trauma, all causing neuronal damage and death. Using a triple transgenic mouse model of AD (3xTg-AD mouse), which bears mutations in APP, PS1 and tau, and shows pathological signs resembling those of AD patients, we studied the pattern of AD-associated retinal degeneration, extending analysis to the retinal pigment epithelium (RPE) and choroid. They were examined deposition of amyloid-? and phospho-tau, TRAIL and its receptors, activated gliosis and microglia, cytokines and COX-2 expression and, finally, the hypoxia-induced angiogenic VEGF factor and apoptotic death. Importantly, pathological signs of 3xTg-AD retinal specimens were compared to those from 3xTg-AD mice that were subjected to a chronic treatment with an anti-TRAIL antibody for 15 months. The results show A? and phospho-tau deposits in the parenchyma and blood vessels of eye structures along with changes in TRAIL system, inflammation and vascular abnormalities, that were all prevented by the treatment with the neutralizing TRAIL antibody. We suggest that the 3xTg-AD mice have AD-associated signs of retinal degeneration and RPE/choroid dysfunction, and TRAIL is central to the aberrant modifications of these structures that benefit from anti-TRAIL treatment.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
