Date of Award
Open Access Dissertation
Melissa A. Moss
Alzheimer’s disease (AD), the most common form of neurodegenerative disorder, is characterized by deposition of amyloid-β (Aβ) plaques in the brain. Aβ monomer undergoes nucleation to form oligomers, then soluble aggregates, then fibrils which make up the plaques. Aβ oligomer species are believed to be the most neurotoxic aggregate species. Currently under investigation is a mechanism for Aβ removal from the brain, across the blood-brain barrier (BBB). P-glycoprotein (P-gp) is a membrane-bound efflux protein located on the apical, or blood, side of the BBB, which transports a wide variety of substrates. Further complicating this potential clearance mechanism is the reduction of P-gp cell surface expression in arteries exhibiting cerebral amyloid angiopathy (CAA), or the buildup of amyloid plaques around the arteries.
P-gp has been suggested as a potential Aβ clearance mechanism based on its ability to transport a wide variety of amphipathic substrates even though experimental evidence of Aβ transport via P-gp has been disputed. This study sought to examine and characterize Aβ aggregate species interaction with P-gp. Additionally, the potential deleterious relationship between P-gp and extended Aβ presence was investigated.
Of the four different Aβ aggregate species tested, monomer, oligomer, sonicated fibril, and fibril, only the Aβ oligomer demonstrated the ability to bind to P-gp. These Aβ oligomers displayed a selective interaction with the R-binding site, and not the H-binding site. However, this binding and interaction could not be confirmed in a cellular transport assay.
Extended Aβ aggregate species treatment at the apical surface of a cellular monolayer revealed no change in either the cell surface expression of P-gp or the transport capabilities of P-gp. Interestingly, when a cellular monolayer was treated from the basolateral surface with Aβ aggregate species, the active P-gp driven net efflux decreased. These results support interactions between Aβ oligomers and P-gp and motivate further investigation of P-gp as a therapeutic clearance mechanism for Aβ.
Holt, H.(2019). Role of P-Glycoprotein in Alzheimer’s Disease for Enhanced Brain Elimination of Amyloid-β. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5218