Effects of transient peripheral immune stimulation on AD pathology

01.09.2015 bis 01.09.2018

Late-onset Alzheimer’s Disease (AD) has been linked to genetic mutations and most recently also epigenetic modifications of a range of immune-related genes (Lambert et al., 2013; de Jager et al., 2014; Lunnon et al., 2014), indicating a significant contribution of immunity to AD pathology. The immune response during AD is largely mediated by the brain’s primary immune cells and resident macrophages, the microglia (Wyss-Coray & Rogers, 2012; Gandy & Heppner, 2013). Importantly, it was recently shown that changes in the microglial immune state could significantly modify AD pathology (e.g. Heneka et al., 2013), indicating that alterations in the microglial immune response can significantly affect disease severity.
While it was previously assumed that the brain is shielded from the periphery by a cellular barrier (the blood-brain barrier), it has recently become clear that inflammatory signals can be transmitted from the periphery to the brain (Perry et al., 2007). Importantly, microglia, the brain’s immune cells, can respond to these signals, leading to acute changes in their behavior. What remains unknown, however, is whether inflammatory events in the periphery can have long-lasting effects on microglial behavior. If this were the case, then any peripheral inflammation, even if it was only temporary, could influence the response of the brain’s immune system to subsequent pathological events in the brain.
In line with this hypothesis, recent data indicate that peripheral infections contribute to the etiology of AD and we have already found that transient peripheral inflammation (as it may occur as part of a bacterial infection for example) can induce long-lasting alterations in the brain’s immune response. Here we want to investigate the mechanism of these changes and analyze how they modulate subsequently developing AD. We will focus on the brain’s primary immune cells, the microglia, and analyze whether these cells can modulate AD-like pathology in mouse models. Further, we will investigate epigenetic modifications, as these have just been identified as strong risk-factors for late-onset AD. These studies could identify novel non-genetic risk factors for AD and thereby aid in alleviating this devastating disease.