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

Zhen Zhao, Abhay P. Sagare, Qingyi Ma, Matthew R. Halliday, Pan Kong, Kassandra Kisler, Ethan A. Winkler, Anita Ramanathan, Takahisa Kanekiyo, Guojun Bu, Nelly Chuqui Owens, Sanket V. Rege, Gabriel Si, Ashim Ahuja, Donghui Zhu, Carol A. Miller, Julie A. Schneider, Manami Maeda, Takahiro Maeda, Tohru SugawaraJustin K. Ichida, Berislav V. Zlokovic

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155 Citations (Scopus)

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-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/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided 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. Inducible pluripotent stem cell-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, which has implications for Aβ brain homeostasis and clearance therapy.

Original languageEnglish
Pages (from-to)978-987
Number of pages10
JournalNature Neuroscience
Volume18
Issue number7
DOIs
Publication statusPublished - Jun 25 2015

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Zhao, Z., Sagare, A. P., Ma, Q., Halliday, M. R., Kong, P., Kisler, K., ... Zlokovic, B. V. (2015). Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nature Neuroscience, 18(7), 978-987. https://doi.org/10.1038/nn.4025