期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 6, 页码 1930-1941出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0350-15.2016
关键词
Alzheimer's disease; blood-brain barrier; P-glycoprotein; transporter; ubiquitin-proteasome system
资金
- National Institute on Aging Grant [1R01AG039621]
- 3M Science and Technology Doctoral Fellowship
- 3M Grant [P01-AG005119-20]
- Division of Intramural Research at National Institute of Environmental Health Sciences/National Institutes of Health
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.
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