P-glycoprotein: a role in the export of amyloid-beta in Alzheimer's disease?

Abstract

The accumulation of amyloid-b (Ab) peptides is a key histopathological feature of the Alzheimer's brain. Defective clearance mechanisms result in toxic levels of soluble Ab40 and Ab42 oligomers, leading to impaired synaptic function, neurodegeneration and cognitive decline. Growing evidence points to the involvement of P-glycoprotein (P-gp or ABCB1), an ATPbinding cassette transporter highly expressed on the luminal side of the blood-brain barrier, in facilitating the clearance of Ab from the brain. In this review, we summarise evidence from human, animal and in vitro studies examining the contribution of P-gp to Ab clearance, and discuss the potential for P-gp as a novel pharmacological target in Alzheimer's disease (AD). P-gp expression and activity in the brain are inversely correlated with ageing, Ab deposition and AD. Moreover, Ab itself has been found to compromise the expression of P-gp, thereby exacerbating Ab deposition and disease. Despite decades of research, the pathophysiology of AD remains elusive. Understanding the normal versus impaired processing and clearance mechanisms affecting Ab peptides will assist the development of more effective therapeutic agents to combat this progressive neurodegenerative condition that continues to devastate millions of patients globally. Show more