Targeting Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand ameliorates retinal pathology in a triple transgenic mouse model of Alzheimer's disease

Cognitive impairment typical of Alzheimer's disease (AD) parallels with failure of an ensemble of CNS functions. In AD, the anomalous protein amyloid-? accumulates in various nervous system areas, including the retina. The proapoptotic/proinflammatory cytokine Tumor Necrosis factor Related Apoptosis-Inducing Ligand (TRAIL) is a potent mediator of stimuli noxious to neurons, such as amyloid-?, brain ischemia, or trauma, all acknowledged to lead to neuronal damage and death. Thus, the effects of chronic anti-TRAIL treatment were investigated in vivo, on retinal pathology affecting the 3xTg-AD mouse. Amyloid-? deposits and microglia/macrophage infiltration were detected throughout the retina/retinal pigment epithelium layers of untreated 15- month-old 3xTg-AD mice. Particularly, amyloid-? was accumulating in retinal blood vessels in quite a prominent manner. In addition, phosphorylated Tau protein was overexpressed in the retina and, eventually, it co-localized with amyloid-?. In the same line, western blot analysis of retinal lysates from untreated 3xTg-AD mice revealed high expression of both amyloid protein precursor (APP) and phospho-Tau, and, moreover, of proinflammatory molecules, such as COX2 and TNFR1. Activation of caspases was also demonstrated in the same samples. Chronic systemic administration of an anti-TRAIL monoclonal antibody significantly improved the outcome of retinal morphological and biochemical parameters in 3xTg-AD mice. Results indicate that amyloid- ?/Tau-related retinal pathology featured by aging 3xTg-AD mice is substantially contributed by an overshooting inflammatory/immune response, and that the latter is efficaciously blunted by the anti- TRAIL treatment, substantially achieving beneficial, protective effects upon the retina. Thus, the TRAIL system may be regarded as a potential target for therapeutic intervention in AD-associated retinal pathology.