| First Author | Zhao Z | Year | 2015 |
| Journal | Nat Neurosci | Volume | 18 |
| Issue | 7 | Pages | 978-87 |
| PubMed ID | 26005850 | Mgi Jnum | J:221101 |
| Mgi Id | MGI:5637941 | Doi | 10.1038/nn.4025 |
| Citation | Zhao Z, et al. (2015) Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat Neurosci 18(7):978-87 |
| abstractText | 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-beta (Abeta) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Abeta clearance across the murine blood-brain barrier (BBB) and accelerated Abeta 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 Abeta bound to the low density lipoprotein receptor related protein-1, a key Abeta clearance receptor, and guided Abeta trafficking to Rab5 and Rab11, leading to Abeta endothelial transcytosis and clearance. PICALM levels and Abeta 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 Abeta clearance. Thus, PICALM regulates Abeta BBB transcytosis and clearance, which has implications for Abeta brain homeostasis and clearance therapy. |
