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Central role for PICALM in amyloid-? blood-brain barrier transcytosis and clearance.


ABSTRACT: PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-? (A?) pathology and cognitive impairment. Moreover, Picalm deficiency diminished A? clearance across the murine blood-brain barrier (BBB) and accelerated A? pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of A? bound to the low density lipoprotein receptor related protein-1, a key A? clearance receptor, and guided A? trafficking to Rab5 and Rab11, leading to A? endothelial transcytosis and clearance. PICALM levels and A? clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced A? clearance. Thus, PICALM regulates A? BBB transcytosis and clearance, which has implications for A? brain homeostasis and clearance therapy.

SUBMITTER: Zhao Z 

PROVIDER: S-EPMC4482781 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/cl  ...[more]

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