Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance

DSpace/Manakin Repository

Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance

Citable link to this page

 

 
Title: Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance
Author: Zhao, Zhen; Sagare, Abhay P.; Ma, Qingyi; Halliday, Matthew R.; Kong, Pan; Kisler, Kassandra; Winkler, Ethan A.; Ramanathan, Anita; Kanekiyo, Takahisa; Bu, Guojun; Owens, Nelly Chuqui; Rege, Sanket V.; Si, Gabriel; Ahuja, Ashim; Zhu, Donghui; Miller, Carol A.; Schneider, Julie A.; Maeda, Manami; Maeda, Takahiro; Sugawara, Tohru; Ichida, Justin K.; Zlokovic, Berislav V.

Note: Order does not necessarily reflect citation order of authors.

Citation: Zhao, Z., A. P. Sagare, Q. Ma, M. R. Halliday, P. Kong, K. Kisler, E. A. Winkler, et al. 2015. “Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance.” Nature neuroscience 18 (7): 978-987. doi:10.1038/nn.4025. http://dx.doi.org/10.1038/nn.4025.
Full Text & Related Files:
Abstract: PICALM is highly validated genetic risk factor for Alzheimer’s disease (AD). Here, we report that PICALM reductions in AD and murine brain endothelium correlate with amyloid–β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminishes Aβ clearance across the murine blood–brain barrier (BBB) and accelerates Aβ pathology that is reversible by endothelial PICALM re–expression. Using human brain endothelial monolayer, we show that PICALM regulates PICALM/clathrin–dependent internalization of Aβ bound to the low density lipoprotein receptor related protein–1, a key Aβ clearance receptor, and guides Aβ trafficking to Rab5 and Rab11 leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD–derived endothelial monolayers, which was reversible by adenoviral–mediated PICALM transfer. iPSC–derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance that has implications for Aβ brain homeostasis and clearance therapy.
Published Version: doi:10.1038/nn.4025
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482781/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983849
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters