Regulatory T cells delay disease progression in a murine model of Alzheimer's disease

Abstract

Vaccines targeting beta-amyloid represent promising strategies for the treatment of AD. Immunization approaches provided encouraging results in mouse models and a subsequent human clinical trial (AN1792). Whereas preclinical studies in murine models did not show evidence of T cell-related side effects, the AN1792 trial had to be interrupted due to the development of meningoencephalitis attributed to pro-inflammatory T cell responses in 6% of the patients. Several reports also suggest that beta-amyloid -specific CD4 + T cells may be implicated in the pathophysiology of AD and could have a strong therapeutic potential as well, further supporting the need for better understanding the role and regulation of T cell responses to beta-amyloid. We previously showed that regulatory T cells (Tregs) critically control the magnitude of beta-amyloid-specific CD4 + T cell responses in both physiological and pathological settings in response to vaccination. However, the actual role of Tregs in the pathophysiology of AD remains unknown. We analyzed the impact of Tregs on disease progression in a murine model of AD. APPPS1 mice were depleted of Treg cells by injecting anti-CD25 antibodies, and the impact of Treg depletion on the neuropathology and cognitive deficits was evaluated. Depletion of Treg cells accelerated the onset of cognitive deficits in APPPS1 mice. Alteration in spatial memory was detected starting from 7 months in Treg-depleted animals, while PBS-treated APPPS1 mice were not yet cognitively impaired as compared to wild-type animals. Early cognitive impairment in Treg-depleted mice was correlated with alterations in the neuroinflammatory response that is associated with disease progression. Treg cells play a beneficial role in the pathophysiology of AD and delay disease progression in a murine model of the disease. These data open new perspectives in the development of Treg-based innovative immunotherapy approaches for the treatment of AD.