A[beta]40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway

• Published in: The Journal of neuroscience 2016-02, Vol.36 (6), p.1930-1941
• Main Authors: Hartz, Anika MS, Zhong, Yu, Wolf, Andrea, Levine, Harry III, Miller, David S, Bauer, Bjorn
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0350-15.2016

Failure to clear amyloid-[beta] (A[beta]) from the brain is in part responsible for A[beta] brain accumulation in Alzheimer's disease (AD). A critical protein for clearing A[beta] across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood-brain barrier in AD, which has been shown to be associated with A[beta] brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nm A[beta]40, A[beta]40, aggregated A[beta]40, and A[beta]42. We observed that only A[beta]40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose- and time-dependent manner. To identify the steps involved in A[beta]-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin-proteasome system, and monitored P-gp protein expression, transport activity, and P-gp-ubiquitin levels. Thus, exposing brain capillaries to A[beta]40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findings may provide potential therapeutic targets within the blood-brain barrier to limit P-gp degradation in AD and improve A[beta] brain clearance.