Immune and injury response in neurodegeneration

Abstract

The aging brain shows prominent cellular and molecular abnormalities, which may predispose or contribute to neurodegeneration. These abnormalities include loss in neural stem cell activity, chronic activation of glial cells, loss of synapses and neurons, and accumulation of proteinacious aggregates. Growing evidence suggests that systemic factors may have a role in some of these age-related changes but the molecular basis of such effects is unclear. To study the effects of systemic factors on brain aging we treat young mice for several weeks with plasma from young or old mice and study their brains for changes in neurogenesis and inflammation. We also pair old and young mice by parabiosis, which facilitates the exchange of blood-derived cells and molecules through a shared blood supply. We analyze plasma from experimental mice for changes in secreted signaling proteins and test the most significantly different factors in cell culture and mouse models for their effects on neurogenesis or microglial function. We found that while exposure of the young brain to an old systemic environment via parabiotic pairing results in more inflammation and a 25% drop in the number of newly born neurons, the old mouse brain that has been exposed to a young systemic environment is less inflamed and has a 3-4-fold increase in neurogenesis. Plasma isolated from old mice inhibits neurogenesis and microglial phagocytosis in cell culture and when injected i.v. over several weeks into young mice reduces neurogenesis, impairs long term potentiation and impairs spatial memory function. Proteomic studies identified several secreted signaling proteins, which are sufficient to inhibit neurogenesis and potently modulate microglial functions in cell culture and in vivo. These studies show that systemic factors in the aging organism are potent regulators of age-related changes in the brain. We demonstrate that specific proteins isolated based on strong correlations with the observed effects are sufficient to modulate neurogenesis and microglial functions. Such factors may be useful in the development of new treatments for age-related neurodegeneration.