Ataxia-telangiectasia (A-T) is a neurodegenerative disease of childhood. Its symptoms include ataxia, cancer susceptibility, hypersensitivity to Ionizing radiation, immune deficiency, sterility and rapid degeneration of neurons in the cerebellar cortexes. As there is no cure for this devastating childhood disease, we aim to study whether inflammation serves as a “second-hit” to drive the disease process as to propose the essential role of immune system in modulation of A-T neuropathology....[ Read more ]

Ataxia-telangiectasia (A-T) is a neurodegenerative disease of childhood. Its symptoms include ataxia, cancer susceptibility, hypersensitivity to Ionizing radiation, immune deficiency, sterility and rapid degeneration of neurons in the cerebellar cortexes. As there is no cure for this devastating childhood disease, we aim to study whether inflammation serves as a “second-hit” to drive the disease process as to propose the essential role of immune system in modulation of A-T neuropathology.

We found that lipopolysaccharide (LPS)-induced inflammation directly led to neurodegeneration of the cerebellar Purkinje neurons in our A-T mouse model. However, LPS failed to accelerate neurodegeneration in A-T cortical neurons even similar activation patterns were observed in cortical microglia and astrocytes, suggesting the regional variation in response to an immune challenge in A-T.

The roles of tumor necrosis factor alpha (TNFα) or interleukin-1 beta (IL1β) in A-T progression was also studied in A-T mouse model. We showed that IL1β, like LPS, could trigger structural damage not only in the cerebellum but also in the cortex. Interestingly, TNFα reversed the abnormalities in A-T Purkinje neurons through MAPK and NFκB pathways. It suggests the immunomodulatory role of TNFα to reverse A-T neuropathology.

The beneficial effect of anti-inflammatory drug ibuprofen was also investigated. We found that ibuprofen attenuated inflammation induced cellular damage and oxidative stress in both in-vitro neuronal culture and in-vivo A-T mouse model. More importantly, ibuprofen rescued inflammation induced motor dysfunction in A-T mice.

Taken together, we believe that pro- and anti-inflammatory cytokine balance is one of the major determinants in neuronal survival and the disease progression. Also, we propose that anti-inflammatory strategy is able to reduce cerebellar damage and prolong lifespan in A-T patient. The current study provides a new approach to understanding the interaction between neurodegeneration and the immune response and suggests the potentiality of immunotherapy to relieve A-T progression.