Aß40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway.
J Neurosci
; 36(6): 1930-41, 2016 Feb 10.
Article
in En
| MEDLINE
| ID: mdl-26865616
ABSTRACT
Failure to clear amyloid-ß (Aß) from the brain is in part responsible for Aß brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aß 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 Aß 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 Aß40, Aß40, aggregated Aß40, and Aß42. We observed that only Aß40 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 Aß-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 Aß40 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 Aß brain clearance. SIGNIFICANCE STATEMENT The mechanism reducing blood-brain barrier P-glycoprotein (P-gp) in Alzheimer's disease is poorly understood. In the present study, we focused on defining this mechanism. We demonstrate that Aß40 drives P-gp ubiquitination, internalization, and proteasome-dependent degradation, reducing P-gp protein expression and transport activity in isolated brain capillaries. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit P-gp degradation in Alzheimer's disease and improve Aß brain clearance.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
/
Blood-Brain Barrier
/
Amyloid beta-Peptides
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Ubiquitin
/
Proteasome Endopeptidase Complex
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Neurosci
Year:
2016
Document type:
Article