The College of Pharmacy Monthly Research Publication Highlight details a novel mechanism by which changes in the blood-brain barrier may contribute to the development of Alzheimer’s disease

April 08, 2016

By Greg Graf

The University of Kentucky (UK) College of Pharmacy Research Publication Highlight for March 2016 is titled “Aβ40 Reduces P-glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway” and was published in The Journal of Neuroscience.

The collaborative project was conducted by investigators from the UK Colleges of Pharmacy and Medicine, the University of Minnesota, Duluth, and the National Institute of Environmental Health Sciences (NIEHS).  The lead author is Dr. Anika Hartz from the UK Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences.  Dr. Hartz’ laboratory works closely with Dr. Björn Bauer’s research team in the Division of Pharmacology and Experimental Therapeutics in the Department of Pharmaceutical Sciences in UK’s College of Pharmacy. Dr. David Miller from the Laboratory of Signal Transduction at the NIEHS, Andrea Wolf from the Department of Pharmacy Practice and Pharmaceutical Sciences at the University of Minnesota, and Drs. Yu Zhong and Harry Le Vine, III, from UK’s Sanders-Brown Center on Aging also contributed to the project.   

Accumulation in brain of b-amyloid protein aggregates contributes to neurodegeneration in the progression of Alzheimer’s disease, but the mechanisms that promote accumulation of these protein aggregates is poorly understood.  Mechanisms for the removal of b-amyloid from the brain include its transport across the blood-brain barrier into the plasma by the multi-drug transporter, P-glycoprotein (P-gp).  Previous work indicates that P-gp levels are reduced in capillary endothelial cells that comprise the blood-brain barrier, but the mechanisms responsible for this reduction were not known.  The present study demonstrates that β-amyloid triggers P-gp reduction by promoting its internalization and degradation by the ubiquitin-proteasome pathway, a system commonly used by cells to remove damaged and excess proteins.  These findings suggest that accumulation of β-amyloid contributes to a reduction in its own clearance, establishing a vicious positive-feedback cycle in which β-amyloid begets accumulation of more b-amyloid in the brain of patients with Alzheimer’s disease.

“These exciting results not only identify a molecular mechanism that may contribute to the progression of Alzheimer’s disease, but also identify a potential point for therapeutic intervention” said Greg Graf, Assistant Dean for Translational Research.