Targeting Beta Amyloid Clearance as Therapeutic Approach for Alzheimer's Disease
Jeffrey Keller, PhD.
Pennington Biomedical Research Center and School of Human Ecology
Funded Project (May 1, 2012 - April 30, 2015)
Pilot Project (Sept. 14, 2011 – April 30, 2012)
ARRA Pilot Project (Sept. 14, 2009 – Sept. 13, 2011)
Significant efforts have been made to elucidate the mechanisms responsible for beta amyloid (Aβ) accumulation in the brain of Alzheimer's disease patients (AD). Possible mechanisms for Aβ pathogenesis include faulty clearance across the blood-brain barrier (BBB). Continuous removal of Aβ from the CNS is important for preventing or delaying Aβ accumulation. Low-density lipoprotein receptor protein-1 (LRP1) and P-glycoprotein (P-gp) are believed to be major Aβ efflux transporters at the BBB, and reduced function of these transporters at the BBB has been observed during normal aging and in AD. A role for LRP1 to Aβ transport across the BBB in AD has been demonstrated, however the specific role and contribution of P-gp to the clearance of Aβ and consequent Aβ toxicity remains largely unknown and poorly defined. Understanding the role of P-gp to Aβ regulation is essential not only for understanding the basis for Aβ fluxes in the brain, but also because it may identify novel roles for P-gp in modulating specific forms or species of Aβ, or potentially serving as a basis for the development of novel therapeutics for regulating the levels of Aβ in the brain. Thus, there is an urgent need to elucidate exact role P-gp plays in the clearance of Aβ. P-gp is an efflux transporter highly expressed at the luminal side of the endothelium at the BBB, reported to play a potential role in regulating Aβ clearance by several groups. The mode of interaction between P-gp and Aβ is undefined, and the mechanism by which P-gp removes Aβ in vivo remains poorly understood, thus further studies in these areas are required to clarify the exact role of P-gp in Aβ regulation in the brain. Our preliminary data confirm a significant role for P-gp in regulating Aβ levels in the brain. Therefore, clarifying such role will be useful to gain valuable clues regarding strategies for treating and/or preventing increased levels of toxic Aβ observed in AD and vascular dementia.