Dementia, including its most common form, Alzheimers disease, has become a major public health issue with 44 million people affected world-wide. New insights in disease pathways have discovered a hard-wired link between the brain and our immune system which is activated following danger signals such as infection, or stress. Under healthy conditions, this immune-to-brain signalling results in transient activation of physiological, metabolic and neuroendocrine pathways that aid our recovery. However, this signalling is not always harmless; elderly or individuals with ongoing CNS diseases show exaggerated responses to these dangers signals as a result of structural and/or functional changes to the brain, making this communication maladaptive. The underlying biological mechanisms of accelerated neuropathology following systemic infection are incompletely understood, but a role for microglia has been suggested from a range of experimental studies, including our studies performed in Southampton. These innate immune cells of the brain become primed in aging and CNS disease and exhibit a lower threshold for activation and following systemic infection these cells secrete increased levels of IL-1b and TNFa in the brain, which is detrimental for neuronal function. These observations have led to the identification of novel therapeutic targets for treatment of Alzheimers disease and thus have clear clinical relevance. For example, cognitive decline in patients with elevated levels of circulating cytokines progress faster when compared to patients with low levels of these pro-inflammatory biomarkers. More importantly, in a small Phase I/II safety study the cognitive decline and other behavioural changes was not as marked as the placebo group following administration of a TNF-a inhibitor (Etanercept), suggesting that blocking this inflammatory immune signal may be beneficial and delay onset of dementia. The BBB is a major obstacle to the delivery of therapeutic antibodies at effective doses to the CNS. Development of disease modifying drugs for neurodegenerative diseases is urgently needed, and recent in vitro and preclinical studies have pursued transporter proteins expressed on the luminal side of the BBB to shuttle large molecular cargos across the BBB. Medimmune has generated a novel technology that increases BBB influx of large biologics up to 10 percent, outperforming technologies from their competitors. In
this studentship we aim to test for the first time if this new technology can be applied to models of systemic infection/inflammation and neurodegeneration, which is increasingly recognised as an important risk factors for developing dementia, caused by Alzheimers diseases or vascular dementia.