Alzheimer’s disease (AD) is the most common form of dementia and a large growing burden on our health system. Although the cause of AD is unknown, the underlying pathology has been well established. A critical factor is the accumulation of amyloid-β (Aβ) peptides in the brain, which are toxic to neurons and impair synaptic function. Experimental treatments to remove Aβ containing plaques have not been translated to the clinic, and new therapeutic avenues aimed at preventing the deposit of Aβ peptides are needed.

The mechanism of export of Aβ peptides from neurons and removal via efflux across the blood brain barrier (BBB) endothelium has been poorly elucidated. Two members of the ABC transporter family have recently been implicated in this process, i.e. ABCB1 (P-glycoprotein) and ABCG4. In addition to a role at the BBB, these pumps may also contribute to the release of Aβ peptides from neuronal cells. Transport of Aβ peptides from both sites has been proposed to form a clearance pathway from the CNS. Moreover, aberrant function of the pumps at either site may result in accumulation of Aβ peptides within the CNS and thereby accelerate the formation of toxic plaques. Both transporters have post-translational regulatory mechanisms in common, which can form the basis for future therapeutic strategies to prevent the deposit of these toxic peptides by increasing the flux through this clearance pathway. Our current experimental aims are to:

• Characterise the role of ABCB1 in the export of Aβ peptides out of neurons
• Unravel the regulation of these transporters, including the post-translational modification via the E3-ubiquitin ligase, NEDD4-1.