The blood-brain barrier provides a number of targets which we can exploit pharmacologically, not only to improve CNS drug delivery, but to restore brain homeostasis and reverse neurodegenerative diseases.
Unravelling the impact of BBB dysfunction on CNS exposure of drugs in neurodegeneration
Many neurodegenerative disorders have been reported to exhibit altered expression and function of efflux transporters such as P-glycoprotein and breast cancer resistance protein, which has the potential to impact on the CNS exposure, efficacy and toxicity of many drugs that are prescribed for patients with these diseases. For example, using mouse models of Alzheimer’s disease, we have demonstrated that the rate of BBB transport of certain drugs is reduced, suggesting that the BBB may become more of a barrier in this disease. Using proteomics, we are now investigating how the BBB transporter proteome differs in various models of motor neurone disease and the impact of such changes on CNS exposure of drugs. Such findings will identify novel drug targeting approaches to enhance the CNS exposure of otherwise impermeable therapeutics for motor neurone disease.
Regulation of BBB transporters to enhance β-amyloid clearance
The brain accumulation of the neurotoxic β-amyloid in Alzheimer’s disease results from poor clearance of the protein. Two key proteins clearing β-amyloid from the brain into the blood across the BBB are low density lipoprotein receptor-related protein 1 (LRP1) and P-glycoprotein (P-gp), which we and others have shown are down-regulated in Alzheimer’s disease. Our laboratory examines the impact of biometals on these transporters, and we are now employing biometal modulators to improve the function of these β-amyloid shuttling pumps. Our studies demonstrate a clear role of biometals in the aberrant clearance of β-amyloid and with our BBB expertise, novel therapeutic approaches are being explored to modulate biometal levels, restore BBB homeostasis and improve disease outcomes.
Fatty acid binding proteins as novel targets in neurodegeneration
Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid with a plethora of cognitively-beneficial effects, however the levels of this essential fatty acid are reduced in Alzheimer’s disease. Our laboratory has identified that the BBB trafficking of DHA is reduced in Alzheimer’s disease and this is a result of attenuated levels of the key DHA-trafficking protein fatty acid binding protein 5 (FABP5). Our laboratory is now exploring approaches to enhance the BBB expression of this critical cytoplasmic protein and the impact on DHA trafficking and cognitive function as well as exploring the molecular factors governing DHA uptake into microglia, the resident immune cell of the CNS, where DHA exhibits its anti-inflammatory effects.
Microglial Kv1.3 as a novel target for neuroinflammation
A major contribution to neurodegeneration in Alzheimer’s disease and Parkinson’s disease is neuroinflammation, mediated by activation of microglia. Activated microglia exhibit increased expression of the voltage gated Kv1.3 channel, which is associated with pro-inflammatory mediator release. Non-selective blockade of Kv1.3 results in beneficial effects in disease models, however, currently available blockers suffer from poor selectivity. Together with Raymond Norton, we are evaluating the impact of very specific and selective peptide-based Kv1.3 blockers on microglial activation and neuroinflammation. Our exciting preliminary data demonstrate that novel peptide based blockers, such as the scorpion-derived HsTX1[R14A], can reduce activated microglial release of pro-inflammatory cytokines.